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Colchicine is a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
used to treat
gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intens ...
and
Behçet's disease Behçet's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the ey ...
. In gout, it is less preferred to NSAIDs or
steroids A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
. Other uses for colchicine include the management of
pericarditis Pericarditis is inflammation of the pericardium, the fibrous sac surrounding the heart. Symptoms typically include sudden onset of sharp chest pain, which may also be felt in the shoulders, neck, or back. The pain is typically less severe when sit ...
and
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 ...
. Colchicine is taken by mouth. Colchicine has a narrow
therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
, so overdosing is a significant risk. Common side effects of colchicine include
gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
upset, particularly at high doses. Severe side effects may include low blood cells and
rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of ...
, and the medication can be deadly in overdose. Whether colchicine is safe for use during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
is unclear, but its use during
breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...
appears to be safe. Colchicine works by decreasing
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
via multiple mechanisms. Colchicine, in the form of the autumn crocus (''Colchicum autumnale''), has been used as early as 1500 BC to treat joint swelling. It was approved for medical use in the United States in 1961. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ...
. In 2020, it was the 241st most commonly prescribed medication in the United States, with more than 1million prescriptions.


Medical uses


Gout

Colchicine is an alternative for those unable to tolerate NSAIDs when treating gout. Low doses appear to be well tolerated and may reduce gout symptoms and pain (1.2 mg in one hour, followed by 0.6 mg an hour later). This low dose may have a similar effectiveness to NSAIDS. At high doses, side effects (primarily diarrhea, nausea, or vomiting) limit its use, however may be effective against pain. In addition, there is preliminary evidence that daily colchicine (0.6 mg twice daily) 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, although adverse gastrointestinal effects may occur. For treating gout symptoms, colchicine is used orally with or without food, as symptoms first appear. Subsequent doses may be needed if symptoms worsen. A 2021 updated Cochrane review found that low-dose colchicine had benefits similar to NSAIDs.


Other conditions

Colchicine is also used as an anti-inflammatory agent for long-term treatment of
Behçet's disease Behçet's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the ey ...
. It appears to have limited effect in
relapsing polychondritis Relapsing polychondritis is a multi-systemic condition characterized by repeated episodes of inflammation and deterioration of cartilage. The often painful disease can cause joint deformity and be life-threatening if the respiratory tract, hear ...
, as it may only be useful for the treatment of chondritis and mild skin symptoms. It is a component of therapy for several other conditions, including pericarditis, pulmonary fibrosis, biliary cirrhosis, various vasculitides, pseudogout, spondyloarthropathies, calcinosis, scleroderma, and amyloidosis. Research regarding the efficacy of colchicine in many of these diseases has not been performed. It is also used in the treatment of
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 ...
, in which it reduces attacks and the long-term risk of
amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weig ...
. Colchicine is effective for prevention of atrial fibrillation after
cardiac surgery Cardiac surgery, or cardiovascular surgery, is surgery on the heart or great vessels performed by cardiac surgeons. It is often used to treat complications of ischemic heart disease (for example, with coronary artery bypass grafting); to co ...
. Potential applications for the anti-inflammatory effect of colchicine have been studied with regard to atherosclerosis and chronic coronary disease (e.g., stable ischemic heart disease). 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.


Contraindications

Long-term ( prophylactic) regimens of oral colchicine are absolutely contraindicated in people with advanced
kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
(including those on dialysis). 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 Polyneuropathy ( poly- + neuro- + -pathy) is damage or disease affecting peripheral nerves (peripheral neuropathy) in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hand ...
. Colchicine toxicity can be potentiated by the concomitant use of
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...
-lowering drugs.


Adverse effects

Deaths – both accidental and intentional – have resulted from overdose of colchicine. Typical side effects of moderate doses may include gastrointestinal upset, diarrhea, and
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...
. High doses can also damage
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
, lead to
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
, and cause hair loss. All of these side effects can result from inhibition of
mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...
, which may include neuromuscular toxicity and
rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of ...
.


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. Colchicine can be toxic when ingested, inhaled, or absorbed in the eyes. It can cause a temporary clouding of the
cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical ...
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 Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
,
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...
, diarrhea, and
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
. This can cause
hypovolemic shock Hypovolemic shock is a form of shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It could be the result of severe dehydration through a variety of mechanisms or blood loss. Hypovolemic shock is a ...
due to extreme vascular damage and fluid loss through the
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
, which can be fatal. 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 Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
; muscular weakness; liver failure; hepatomegaly; bone marrow suppression;
thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...
; and ascending paralysis leading to potentially fatal
respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
. Neurologic symptoms are also evident, including
seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...
, confusion, and
delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...
; children may experience
hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...
s. Recovery may begin within six to eight days and begins with rebound leukocytosis and alopecia as organ functions return to normal. Long-term exposure to colchicine can lead to toxicity, particularly of the
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
,
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
, and
nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the ...
s. Effects of long-term colchicine toxicity include
agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...
, thrombocytopenia, low white blood cell counts,
aplastic anemia Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red bloo ...
, alopecia,
rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...
,
purpura Purpura () is a condition of red or purple discolored spots on the skin that do not blanch on applying pressure. The spots are caused by bleeding underneath the skin secondary to platelet disorders, vascular disorders, coagulation disorders, ...
, vesicular dermatitis, kidney damage, anuria,
peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
, and
myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This me ...
. 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, and may require gastrointestinal decontamination with
activated charcoal "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016). Background In an inter ...
or
gastric lavage Gastric lavage, also commonly called stomach pumping or gastric irrigation, is the process of cleaning out the contents of the stomach. Since its first recorded use in early 19th century, it has become one of the most routine means of eliminating p ...
. Because colchicine is so toxic, chemists are continuing to try to synthesize derivatives of the molecule that decrease the toxicity. The most important aspect of these derivatives is that they keep the tropolone ring (the ring with the methoxy group and the carbonyl) intact to retain the mechanistic properties of the molecule.


Mechanism of toxicity

With overdoses, colchicine becomes toxic as an extension of its cellular mechanism of action via binding to tubulin. Cells so affected undergo impaired protein assembly with reduced
endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. ...
,
exocytosis Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use ...
, cellular motility, and interrupted function of heart cells, culminating in multiple organ failure.


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.


Drug interactions

Colchicine interacts with the
P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
transporter, and the
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
involved in drug and toxin metabolism. Fatal drug interactions have occurred when colchicine was taken with other drugs that inhibit P-glycoprotein and CYP3A4, such as
erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used durin ...
or clarithromycin. People taking
macrolide antibiotic The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...
s,
ketoconazole Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous ca ...
, 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. Symptoms of toxicity include gastrointestinal upset, fever, muscle pain, low blood cell counts, and organ failure. People with
HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
taking atazanavir,
darunavir Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or ...
, fosamprenavir, indinavir,
lopinavir Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir ( lopinavir/ritonavir). It was patented in 1995 and approved for medica ...
, nelfinavir, ritonavir, or saquinavir may experience colchicine toxicity. Grapefruit juice and statins can also increase colchicine concentrations.


Pharmacology


Mechanism of action

In gout, inflammation in
joint A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...
s results from the precipitation of circulating uric acid, exceeding its
solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...
in blood and depositing as crystals of monosodium urate in and around
synovial fluid Synovial fluid, also called synovia, elp 1/sup> is a viscous, non-Newtonian fluid found in the cavities of synovial joints. With its egg white–like consistency, the principal role of synovial fluid is to reduce friction between the articul ...
and
soft tissue Soft tissue is all the tissue in the body that is not hardened by the processes of ossification or calcification such as bones and teeth. Soft tissue connects, surrounds or supports internal organs and bones, and includes muscle, tendons, ...
s of joints. These crystal deposits cause inflammatory arthritis, which is initiated and sustained by mechanisms involving various proinflammatory mediators, such as
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s. Colchicine accumulates in white blood cells and affects them in a variety of ways - decreasing motility, mobilization (especially
chemotaxis Chemotaxis (from '' chemo-'' + '' taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
), and adhesion. Under preliminary research are various mechanisms by which colchicine may interfere with gout inflammation: * Inhibits
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 1 ...
polymerization by binding to its constitutive protein, tubulin * As availability of tubulin is essential to
mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...
, colchicine may inhibit mitosis * Inhibits activation and migration of
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s to sites of inflammation * Interferes with the inflammasome complex found in neutrophils and
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s that mediate interleukin-1β activation, a component of inflammation * Inhibits
superoxide anion In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of th ...
production in response to urate crystals * Interrupts mast cell and
lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane p ...
degranulation Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including gra ...
* Inhibits release of glycoproteins that promote chemotaxis from synovial cells and neutrophils Generally, colchicine appears to inhibit multiple proinflammatory mechanisms, while enabling increased levels of
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
mediators. 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.


Pharmacokinetics

Colchicine appears to be a peripherally selective drug with limited
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
uptake due to binding to
P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
.


History

The plant source of colchicine, the autumn crocus ('' Colchicum autumnale''), was described for treatment of
rheumatism Rheumatism or rheumatic disorders are conditions causing chronic, often intermittent pain affecting the joints or connective tissue. Rheumatism does not designate any specific disorder, but covers at least 200 different conditions, including ar ...
and swelling in the Ebers Papyrus (''circa'' 1500 BC), an
Egypt Egypt ( ar, مصر , ), officially the Arab Republic of Egypt, is a List of transcontinental countries, transcontinental country spanning the North Africa, northeast corner of Africa and Western Asia, southwest corner of Asia via a land bridg ...
ian medical text. It is a toxic
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...
and secondary metabolite. ''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

* * {{Portal bar , Medicine Acetamides Alkaloids Antigout agents Glycine receptor antagonists Heptalenes Microtubule inhibitors Orphan drugs Peripherally selective drugs Pyrogallol ethers Wikipedia medicine articles ready to translate Takeda Pharmaceutical Company brands Tropones Plant toxins