Colchicine
Encyclopedia
Colchicine is a medication used for gout
. It 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
, familial Mediterranean fever
, pericarditis
and Behçet's disease
. It is also being investigated for its use as an anti-cancer
drug.
Oral colchicine has been used for many years as an unapproved drug with no prescribing information, dosage recommendations, or drug interaction warnings approved by the U.S. Food and Drug Administration
(FDA). On July 30, 2009 the FDA approved colchicine as a monotherapy for the treatment of familial Mediterranean fever and acute gout flares, 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.
, was described for treatment of rheumatism
and swelling
in the Ebers Papyrus
(ca. 1500 B.C.), an Egyptian
medical papyrus
. The use of the bulb-like corm
s of Colchicum for gout probably traces back to ca. 550 A.D., as the "hermodactyl" recommended by Alexander of Tralles
. Colchicum extract was first described as a treatment for gout
in De Materia Medica by Pedanius Dioscorides in the first century CE
. Colchicum corms were used by the Persian
physician ibn Sina (Avicenna)
and other Islam
ic physicians, were recommended by Ambroise Pare
in the sixteenth century, and appeared in the London Pharmacopoeia of 1618. Colchicum plants were brought to America
by Benjamin Franklin
, who suffered from gout himself and had written humorous doggerel
about the disease during his stint as Envoy
to France
.
Colchicine was first isolated in 1820 by the French
chemists P.S. Pelletier and J. Caventon. In 1833, P.L. Geiger purified an active ingredient, which he named colchicine. The chemical 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
.
, one of the main constituents of microtubule
s. 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.
The mitosis
inhibiting function of colchicine has been of great use in the study of cellular genetics
. To see the chromosome
s of a cell under a light microscope, it is important that they be viewed near the point in the cell cycle
in which they are most dense. This occurs near the middle of mitosis
, so mitosis must be stopped before it completes. Adding colchicine to a culture during mitosis is part of the standard procedure for doing karyotype
studies.
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.
.
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
.
of a colchicine congener, ZD6126
(also known as ANG453) as a treatment for cancer
.
Colchicine is "used widely" off-label by naturopaths for a number of treatments, including the treatment of back pain.
. High doses can also damage bone marrow
and lead to anemia
. Note that all of these side effects can result from hyperinhibition of mitosis.
A main side effect associated with all mitotic inhibitors is peripheral neuropathy which is a numbness or tingling in the hands and feet due to peripheral nerve damage which can becomes so severe that reduction in dosage or complete cessation of the drug may be required. Microtubules are involved in vesicular transport. In normal cells, Brownian motion sets the stage for the vesicles to reach their destination. Peripheral nerves are among the longest in the body. Brownian motion is not significant enough in these peripheral nerves to allow vesicles to reach their destination. Thus, they are susceptible to microtubule toxins.
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.
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.,
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 gamete
s 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.
When such a tetraploid plant is crossed with a diploid plant, the triploid offspring will usually be sterile
(unable to produce fertile
seed
s or spore
s), although many triploids can be propagated vegetatively
. Growers of annual
triploid plants not readily propagated must buy fresh seed from a supplier each year. Many sterile triploid plants, including some tree
and shrub
s, are becoming increasingly valued in horticulture
and landscaping
because they do not become invasive species
. 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 fruit production.
Colchicine's ability 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.
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. Also, seeds can be presoaked in a colchicine solution before planting. Another way to induce polyploidy is to chop off the tops of plants and carefully examine the regenerating lateral shoots and suckers to see if any look different. If no visual difference is evident, flow cytometry
can be used for analysis.
Doubling of plant chromosome numbers also occurs spontaneously in nature, with many familiar plants being fertile polyploids
. Natural hybridization between fertile parental plants of different levels of polyploidy can produce new plants at an intermediate level, such as a triploid produced by crossing between a diploid and a tetraploid, or a hexaploid produced by crossing between a diploid and an octoploid.
as a generic drug
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 $0.09 to $4.85 per pill.
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 (RCT). That year the FDA started their "Unapproved Drugs Initiative
", through which they sought more rigorous testing of efficacy and safety of colchicine and other unapproved drugs on the market. 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
, based in part on URL-funded research in 2007, including pharmacokinetic studies and a randomized control trial with 185 patients with acute gout. URL Pharma also received seven years of market exclusivity for Colcrys in treatment of familial Mediterranean fever
, under the Orphan Drug Law. URL Pharma then raised the price per pill 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. (In a similar case, thalidomide
was approved in 1998 as an orphan drug for leprosy
and in 2006 for multiple myeloma
.)
In April 2010, in an editorial in the New England Journal of Medicine
(NEJM), A.S. Kesselheim and D.H. Solomon said that the rewards of this legislation are not calibrated to the quality or value of the information produced, that there is no evidence of meaningful improvement to public health, that it would be much less expensive for the FDA or National Institutes of Health
to pay for trials themselves on widely available drugs such as colchicine, and that the cost burden falls primarily on patients or their insurers. URL Pharma posted a detailed rebuttal of the NEJM editorial.
In September 2010, the FDA ordered a halt to marketing of unapproved single-ingredient oral colchicine.
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
. It is a toxic natural product
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...
and secondary metabolite
Secondary metabolite
Secondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of an organism. Unlike primary metabolites, absence of secondary metabolities does not result in immediate death, but rather in long-term impairment of the organism's...
, originally extracted from plants of the genus Colchicum
Colchicum
Colchicum is a genus of flowering plants containing around sixty species of perennial plants which grow from corms. It is a member of family Colchicaceae, and is native to West Asia, Europe and parts of the Mediterranean coast....
(autumn crocus
Autumn Crocus
Autumn Crocus may refer to:*One of two species of flowering plant:** the Autumn Crocus Crocus nudiflorus** the Meadow Saffron Colchicum autumnale, which is also known as Autumn Crocus* Autumn Crocus , a 1931 play by Dodie Smith...
, Colchicum autumnale, also known as "meadow saffron"). It was used originally to treat rheumatic complaints, especially gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
, and still finds use for these purposes today despite dosing issues concerning its toxicity. It was also prescribed for its cathartic
Cathartic
In medicine, a cathartic is a substance that accelerates defecation. This is in contrast to a laxative, which is a substance which eases defecation, usually by softening feces. It is possible for a substance to be both a laxative and a cathartic...
and emetic effects. Colchicine's present medicinal use is in the treatment of gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
, familial Mediterranean fever
Familial Mediterranean fever
Familial Mediterranean fever is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in MEFV, a gene which encodes a 781–amino acid protein denoted pyrin....
, pericarditis
Pericarditis
Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...
and Behçet's disease
Behçet's disease
Behçet's disease is a rare immune-mediated systemic vasculitis that often presents with mucous membrane ulceration and ocular involvements...
. It is also being investigated for its use as an anti-cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
drug.
Oral colchicine has been used for many years as an unapproved drug with no prescribing information, dosage recommendations, or drug interaction warnings approved by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA). On July 30, 2009 the FDA approved colchicine as a monotherapy for the treatment of familial Mediterranean fever and acute gout flares, 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
Probenecid
Probenecid is a uricosuric drug that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.Probenecid was developed as an alternative to caronamide...
has been FDA approved prior to 1982.
History
The plant source of colchicine, the autumn crocus (Colchicum autumnale)Colchicum autumnale
Colchicum autumnale, commonly known as autumn crocus, meadow saffron or naked lady, is a flower which resembles the true crocuses, but flowering in autumn...
, was described for treatment of rheumatism
Rheumatism
Rheumatism or rheumatic disorder is a non-specific term for medical problems affecting the joints and connective tissue. The study of, and therapeutic interventions in, such disorders is called rheumatology.-Terminology:...
and swelling
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
in the Ebers Papyrus
Ebers papyrus
The Ebers Papyrus, also known as Papyrus Ebers, is an Egyptian medical papyrus dating to circa 1550 BC. Among the oldest and most important medical papyri of ancient Egypt, it was purchased at Luxor, in the winter of 1873–74 by Georg Ebers...
(ca. 1500 B.C.), an Egyptian
Egypt
Egypt , officially the Arab Republic of Egypt, Arabic: , is a country mainly in North Africa, with the Sinai Peninsula forming a land bridge in Southwest Asia. Egypt is thus a transcontinental country, and a major power in Africa, the Mediterranean Basin, the Middle East and the Muslim world...
medical papyrus
Papyrus
Papyrus is a thick paper-like material produced from the pith of the papyrus plant, Cyperus papyrus, a wetland sedge that was once abundant in the Nile Delta of Egypt....
. The use of the bulb-like corm
Corm
A corm is a short, vertical, swollen underground plant stem that serves as a storage organ used by some plants to survive winter or other adverse conditions such as summer drought and heat ....
s of Colchicum for gout probably traces back to ca. 550 A.D., as the "hermodactyl" recommended by Alexander of Tralles
Alexander of Tralles
Alexander of Tralles in Lydia was one of the most eminent of the ancient physicians. His date may safely be put in the 6th century, for he mentions Aëtius Amidenus, who probably did not write until the end of the 5th or the beginning of the 6th century, and he is himself quoted by Paul of...
. Colchicum extract was first described as a treatment for gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
in De Materia Medica by Pedanius Dioscorides in the first century CE
Common Era
Common Era ,abbreviated as CE, is an alternative designation for the calendar era originally introduced by Dionysius Exiguus in the 6th century, traditionally identified with Anno Domini .Dates before the year 1 CE are indicated by the usage of BCE, short for Before the Common Era Common Era...
. Colchicum corms were used by the Persian
Iran
Iran , officially the Islamic Republic of Iran , is a country in Southern and Western Asia. The name "Iran" has been in use natively since the Sassanian era and came into use internationally in 1935, before which the country was known to the Western world as Persia...
physician ibn Sina (Avicenna)
Avicenna
Abū ʿAlī al-Ḥusayn ibn ʿAbd Allāh ibn Sīnā , commonly known as Ibn Sīnā or by his Latinized name Avicenna, was a Persian polymath, who wrote almost 450 treatises on a wide range of subjects, of which around 240 have survived...
and other Islam
Islam
Islam . The most common are and . : Arabic pronunciation varies regionally. The first vowel ranges from ~~. The second vowel ranges from ~~~...
ic physicians, were recommended by Ambroise Pare
Ambroise Paré
Ambroise Paré was a French surgeon. He was the great official royal surgeon for kings Henry II, Francis II, Charles IX and Henry III and is considered as one of the fathers of surgery and modern forensic pathology. He was a leader in surgical techniques and battlefield medicine, especially the...
in the sixteenth century, and appeared in the London Pharmacopoeia of 1618. Colchicum plants were brought to America
North America
North America is a continent wholly within the Northern Hemisphere and almost wholly within the Western Hemisphere. It is also considered a northern subcontinent of the Americas...
by Benjamin Franklin
Benjamin Franklin
Dr. Benjamin Franklin was one of the Founding Fathers of the United States. A noted polymath, Franklin was a leading author, printer, political theorist, politician, postmaster, scientist, musician, inventor, satirist, civic activist, statesman, and diplomat...
, who suffered from gout himself and had written humorous doggerel
Doggerel
Doggerel is a derogatory term for verse considered of little literary value. The word probably derived from dog, suggesting either ugliness, puppyish clumsiness, or unpalatability in the 1630s.-Variants:...
about the disease during his stint as Envoy
United States Ambassador to France
This article is about the United States Ambassador to France. There has been a United States Ambassador to France since the American Revolution. The United States sent its first envoys to France in 1776, towards the end of the four-centuries-old Bourbon dynasty...
to France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
.
Colchicine was first isolated in 1820 by the French
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
chemists P.S. Pelletier and J. Caventon. In 1833, P.L. Geiger purified an active ingredient, which he named colchicine. The chemical was later identified as a tricyclic alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
, and its pain-relieving and anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
effects for gout were linked to its ability to bind with tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
.
Biological function
Colchicine inhibits microtubule polymerization by binding to tubulinTubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
, one of the main constituents of microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
s. Availability of tubulin is essential to mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
, and therefore colchicine effectively functions as a "mitotic poison" or spindle poison
Spindle poison
A spindle poison, also known as a spindle toxin, is a poison which disrupts cell division by affecting the protein threads which connect the centromere regions of chromosomes, known as spindles.Some spindle poisons:* Mebendazole* Colchicine...
. 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
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agents) limited by its toxicity against normal cells.
The mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
inhibiting function of colchicine has been of great use in the study of cellular genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
. To see the chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s of a cell under a light microscope, it is important that they be viewed near the point in the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
in which they are most dense. This occurs near the middle of mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
, so mitosis must be stopped before it completes. Adding colchicine to a culture during mitosis is part of the standard procedure for doing karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
studies.
Apart from inhibiting mitosis (a process heavily dependent on cytoskeletal changes), colchicine also inhibits neutrophil
Neutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...
motility and activity, leading to a net anti-inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
effect.
Indications
Colchicine has a relatively low therapeutic indexTherapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
.
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
Familial Mediterranean fever
Familial Mediterranean fever is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in MEFV, a gene which encodes a 781–amino acid protein denoted pyrin....
. 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
Behçet's disease
Behçet's disease is a rare immune-mediated systemic vasculitis that often presents with mucous membrane ulceration and ocular involvements...
.
Off-label uses
The British drug development company Angiogene is developing a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
of a colchicine congener, ZD6126
ZD6126
ZD6126 is a vascular-targeting agent and a prodrug of N-acetylcolchinol, related to colchicine. It has shown promising results on tumors in mice....
(also known as ANG453) as a treatment for cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
Colchicine is "used widely" off-label by naturopaths for a number of treatments, including the treatment of back pain.
Contraindications
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)Side effects
Side effects include gastrointestinal upset and neutropeniaNeutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
. High doses can also damage bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
and lead to anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Note that all of these side effects can result from hyperinhibition of mitosis.
A main side effect associated with all mitotic inhibitors is peripheral neuropathy which is a numbness or tingling in the hands and feet due to peripheral nerve damage which can becomes so severe that reduction in dosage or complete cessation of the drug may be required. Microtubules are involved in vesicular transport. In normal cells, Brownian motion sets the stage for the vesicles to reach their destination. Peripheral nerves are among the longest in the body. Brownian motion is not significant enough in these peripheral nerves to allow vesicles to reach their destination. Thus, they are susceptible to microtubule toxins.
Toxicity
Colchicine poisoning has been compared to arsenicArsenic
Arsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...
poisoning; symptoms start 2 to 5 hours after the toxic dose has been ingested and include burning in the mouth and throat, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
and kidney failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. 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
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
; muscular weakness; and respiratory failure
Respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
. 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 tropoloneTropolone
Tropolone is a derivative of tropone with a hydroxyl group in the 2-position.Two methods for the synthesis of tropolone are by bromination of 1,2-cycloheptanedione with N-bromosuccinimide followed by dehydrohalogenation at elevated temperatures and by acyloin condensation of the ethyl ester of...
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
Tropolone
Tropolone is a derivative of tropone with a hydroxyl group in the 2-position.Two methods for the synthesis of tropolone are by bromination of 1,2-cycloheptanedione with N-bromosuccinimide followed by dehydrohalogenation at elevated temperatures and by acyloin condensation of the ethyl ester of...
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.,
Botanical use
Since chromosome segregationChromosome segregation
Chromosome segregation is a step in cell reproduction or division, where chromosomes pair off with their similar homologous chromosome. In mitosis, a complete copy of each one is made. In meiosis, one chromosome from each pair migrates to opposite ends of the cell and the genes are split to make a...
is driven by microtubules, colchicine is also used for inducing polyploidy in plant cells during cellular division by inhibiting chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
segregation during meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
; half the resulting gamete
Gamete
A gamete is a cell that fuses with another cell during fertilization in organisms that reproduce sexually...
s 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.
When such a tetraploid plant is crossed with a diploid plant, the triploid offspring will usually be sterile
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
(unable to produce fertile
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
seed
Seed
A seed is a small embryonic plant enclosed in a covering called the seed coat, usually with some stored food. It is the product of the ripened ovule of gymnosperm and angiosperm plants which occurs after fertilization and some growth within the mother plant...
s or spore
Spore
In biology, a spore is a reproductive structure that is adapted for dispersal and surviving for extended periods of time in unfavorable conditions. Spores form part of the life cycles of many bacteria, plants, algae, fungi and some protozoa. According to scientist Dr...
s), although many triploids can be propagated vegetatively
Vegetative reproduction
Vegetative reproduction is a form of asexual reproduction in plants. It is a process by which new individuals arise without production of seeds or spores...
. Growers of annual
Annual plant
An annual plant is a plant that usually germinates, flowers, and dies in a year or season. True annuals will only live longer than a year if they are prevented from setting seed...
triploid plants not readily propagated must buy fresh seed from a supplier each year. Many sterile triploid plants, including some tree
Tree
A tree is a perennial woody plant. It is most often defined as a woody plant that has many secondary branches supported clear of the ground on a single main stem or trunk with clear apical dominance. A minimum height specification at maturity is cited by some authors, varying from 3 m to...
and shrub
Shrub
A shrub or bush is distinguished from a tree by its multiple stems and shorter height, usually under 5–6 m tall. A large number of plants may become either shrubs or trees, depending on the growing conditions they experience...
s, are becoming increasingly valued in horticulture
Horticulture
Horticulture is the industry and science of plant cultivation including the process of preparing soil for the planting of seeds, tubers, or cuttings. Horticulturists work and conduct research in the disciplines of plant propagation and cultivation, crop production, plant breeding and genetic...
and landscaping
Landscaping
Landscaping refers to any activity that modifies the visible features of an area of land, including:# living elements, such as flora or fauna; or what is commonly referred to as gardening, the art and craft of growing plants with a goal of creating a beautiful environment within the landscape.#...
because they do not become invasive species
Invasive species
"Invasive species", or invasive exotics, is a nomenclature term and categorization phrase used for flora and fauna, and for specific restoration-preservation processes in native habitats, with several definitions....
. In certain species, colchicine-induced triploidy has been used to create "seedless" fruit, such as seedless watermelons (Citrullus lanatus)
Watermelon
Watermelon is a vine-like flowering plant originally from southern Africa. Its fruit, which is also called watermelon, is a special kind referred to by botanists as a pepo, a berry which has a thick rind and fleshy center...
. Since most triploids do not produce pollen themselves, such plants usually require cross-pollination
Pollination
Pollination is the process by which pollen is transferred in plants, thereby enabling fertilisation and sexual reproduction. Pollen grains transport the male gametes to where the female gamete are contained within the carpel; in gymnosperms the pollen is directly applied to the ovule itself...
with a diploid parent to induce fruit production.
Colchicine's ability to induce polyploidy can be also exploited to render infertile hybrids fertile, for example in breeding triticale (× Triticosecale)
Triticale
Triticale is a hybrid of wheat and rye first bred in laboratories during the late 19th century. The grain was originally bred in Scotland and Sweden. Commercially available triticale is almost always a second generation hybrid, i.e., a cross between two kinds of primary triticales...
from wheat (Triticum spp.)
Wheat
Wheat is a cereal grain, originally from the Levant region of the Near East, but now cultivated worldwide. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...
and rye (Secale cereale)
Rye
Rye is a grass grown extensively as a grain and as a forage crop. It is a member of the wheat tribe and is closely related to barley and wheat. Rye grain is used for flour, rye bread, rye beer, some whiskeys, some vodkas, and animal fodder...
. Wheat is typically tetraploid and rye diploid, with their triploid hybrid infertile; treatment of triploid triticale with colchicine gives fertile hexaploid triticale.
When used to induce polyploidy
Polyploidy
Polyploid is a term used to describe cells and organisms containing more than two paired sets of chromosomes. Most eukaryotic species are diploid, meaning they have two sets of chromosomes — one set inherited from each parent. However polyploidy is found in some organisms and is especially common...
in plants, colchicine cream is usually applied to a growth point of the plant, such as an apical tip, shoot, or sucker. Also, seeds can be presoaked in a colchicine solution before planting. Another way to induce polyploidy is to chop off the tops of plants and carefully examine the regenerating lateral shoots and suckers to see if any look different. If no visual difference is evident, flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
can be used for analysis.
Doubling of plant chromosome numbers also occurs spontaneously in nature, with many familiar plants being fertile polyploids
Polyploidy
Polyploid is a term used to describe cells and organisms containing more than two paired sets of chromosomes. Most eukaryotic species are diploid, meaning they have two sets of chromosomes — one set inherited from each parent. However polyploidy is found in some organisms and is especially common...
. Natural hybridization between fertile parental plants of different levels of polyploidy can produce new plants at an intermediate level, such as a triploid produced by crossing between a diploid and a tetraploid, or a hexaploid produced by crossing between a diploid and an octoploid.
Marketing exclusivity in the United States
As a drug predating the FDA, colchicine was sold in the United StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
as a generic drug
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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 $0.09 to $4.85 per pill.
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 (RCT). That year the FDA started their "Unapproved Drugs Initiative
Unapproved Drugs Initiative
Unapproved Drugs Initiative is a programme by the U.S Food and Drug Administration announced in June 2006 to remove unapproved drugs from the market. some 14 categories of drugs have been affected....
", through which they sought more rigorous testing of efficacy and safety of colchicine and other unapproved drugs on the market. 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
Drug Price Competition and Patent Term Restoration Act
-Overview:The Drug Price Competition and Patent Term Restoration Act, informally known as the "Hatch-Waxman Act" [Public Law 98-417], is a 1984 United States federal law which established the modern system of generic drugs...
, based in part on URL-funded research in 2007, including pharmacokinetic studies and a randomized control trial with 185 patients with acute gout. URL Pharma also received seven years of market exclusivity for Colcrys in treatment of familial Mediterranean fever
Familial Mediterranean fever
Familial Mediterranean fever is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in MEFV, a gene which encodes a 781–amino acid protein denoted pyrin....
, under the Orphan Drug Law. URL Pharma then raised the price per pill 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
Medicaid is the United States health program for certain people and families with low incomes and resources. It is a means-tested program that is jointly funded by the state and federal governments, and is managed by the states. People served by Medicaid are U.S. citizens or legal permanent...
programs from $1 million to $50 million. (In a similar case, thalidomide
Thalidomide
Thalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
was approved in 1998 as an orphan drug for leprosy
Leprosy
Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...
and in 2006 for multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
.)
In April 2010, in an editorial in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
(NEJM), A.S. Kesselheim and D.H. Solomon said that the rewards of this legislation are not calibrated to the quality or value of the information produced, that there is no evidence of meaningful improvement to public health, that it would be much less expensive for the FDA or National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
to pay for trials themselves on widely available drugs such as colchicine, and that the cost burden falls primarily on patients or their insurers. URL Pharma posted a detailed rebuttal of the NEJM editorial.
In September 2010, the FDA ordered a halt to marketing of unapproved single-ingredient oral colchicine.
External links
- Feature on colchicine, by Matthew J. Dowd at vcu.edu
- NIOSH Emergency Response Database