General Description
Odorless or nearly odorless pale yellow needles or powder that darkens on exposure to light. Used to treat gouty arthritis, pseudogout, sarcoidal arthritis and calcific tendinitis.
Reactivity Profile
COLCHICINE(64-86-8) darkens on exposure to light. Incompatible with strong oxidizing agents. Also incompatible with mineral acids .
Air & Water Reactions
Slowly hydrolyzed in acidic solution, but unbuffered solutions are stable at 68°F for at least six months. Isomerizes on exposure to ultraviolet radiation.
Hazard
As little as 20 mg may be fatal if ingested.
Health Hazard
COLCHICINE is classified as super toxic. Probable oral lethal dose in humans is less than 5 mg/kg, i.e. less than 7 drops for a 70 kg (150 lb.) person. Death results from respiratory arrest. The fatal dose varies considerably; as little as 7 mg of colchicine has proved fatal.
Potential Exposure
Colchicine is a drug used to treat gouty arthritis, pseudogout, sarcoidal arthritis; and calcific tendonitis.
First aid
This material is an alkaloid. If this chemical gets into the eyes, remove any contact lenses at once and irrigate immediately for at least 15 minutes, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts the skin, remove contaminated clothing and wash immediately with soap and water. Seek medical attention immediately. If this chemical has been inhaled, remove from exposure, begin rescue breathing (using universal precautions, including resuscitation 894 Colchicine mask) if breathing has stopped and CPR if heart action has stopped. Transfer promptly to a medical facility. When this chemical has been swallowed, get medical attention. Give large quantities of water and induce vomiting. Do not make an unconscious person vomit. Medical observation is recommended for 24 to 48 hours after breathing overexposure, as pulmonary edema may be delayed. As first aid for pulmonary edema, a doctor or authorized paramedic may consider administering a drug or other inhalation therapy
Shipping
UN1544 Alkaloids, solid, n.o.s. or Alkaloid salts, solid, n.o.s. poisonous, Hazard Class: 6.1; Labels: 6.1- Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials
Incompatibilities
Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides, mineral acids. Keep away from light.
Description
Colchicine is a pale-yellow powder that is obtained from various species of Colchicum, primarily Colchicum
autumnale L. Its total chemical synthesis has been achieved, but the primary source of colchicine currently remains alcohol
extraction of the alkaloid from the corm and seed of C. autumnale L. It darkens on exposure to light and possesses
Physical properties
Appearance: colchicine exists in white or light-yellow crystal powder with no smell, and it is seldom prone to absorb moisture. Melting point: it becomes dark when it is exposed to light, and it melts at 87–89?°C. Solubility: this product is soluble in chloroform or ethanol and it dissolves in water. However, the semihydrate crystal can form in certain concentrations. The product is hardly soluble in ether. Specific optical rotation: ?121° (0.9?g/100?mL, chloroform, 589.3?nm, 17?°C).
History
Meadow saffron (Colchicum) is recorded to treat rheumatic swelling on ancient
Egyptian medical papyrus in 1500 B.C.. According to De Materia Medica written by Pedanius Dioscorides in the first century, extract of Meadow saffron is used
in treating gout. London Pharmacopoeia in 1618 recorded that colchicine is also
applied to treat gout.
In 1820, the ingredient was first isolated by the French chemist P.S. Pelletier and
J.B. Caventou. In 1833, it was purified and named by Geiger. Michael Dewar
guessed that there are two seven-membered rings in colchicine in 1945. Murray
Vernon King et al. determined the structure of colchicine by X-ray diffraction in
1952. In 1959, Albert Eschenmoser integrated the product successfully
Colchicine tablet and raw material are approved mostly in domestic in 2010. The
tablet produced by Taiwan manufacturers is approved for being listed in mainland
of China in 2012. The raw material made by Indian obtained the approval in 2013.
There are three kinds of colchicine approved by FDA: with the combination of probenecid, it is prior to be approved. The others are tablet (2009) and capsule (2014).
Indications
Colchicine, an alkaloid obtained from the autumn
crocus, has long been used and is relatively selective for
the treatment of acute gouty arthritis. Unlike many of
the newer agents for use in gout, colchicine has minimal
effects on uric acid synthesis and excretion; it decreases
inflammation associated with this disorder. It is thought
that colchicine somehow prevents the release of the
chemotactic factors and/or inflammatory cytokines from
the neutrophils, and this in turn decreases the attraction
of more neutrophils into the affected area .The
ability of colchicine to bind to leukocyte microtubules
in a reversible covalent complex and cause their depolymerization
also may be a factor in decreasing the
attraction of the motile leukocytes into the inflamed
area.
Biological Functions
Acting on
polymorphonuclear leukocytes and diminishing phagocytosis, it inhibits the production of lactic acid, causing an
increase in the pH of synovial tissue and, thus, a decrease in urate deposition, because uric acid is more soluble at
the higher pH. Additionally, colchicine inhibits the release of lysosomal enzymes during phagocytosis that also
contributes to the reduction of inflammation. Because colchicine does not lower serum urate levels, it has been found
to be beneficial to combine colchicine with a uricosuric agent, particularly probenecid. It is a potent drug, being
effective at doses of approximately 1 mg, but doses as small as 7 mg have caused fatalities.
Biological Activity
Plant-derived alkaloid that binds to tubulin and depolymerizes microtubules.
Biochem/physiol Actions
Colchicine interacts with albumin and binds to tubulin. Its association with tubulin impacts autophagic vacuole fusion with lysosomes. It inhibits tyrosine kinases and phospholipases. Colchicine may be useful for treating acute coronary syndromes. It is prescribed for treating rheumatologic conditions including familial mediterranean fever (FMF) and acute gouty arthritis.
Mechanism of action
Colchicine is rapidly absorbed after oral administration
and tends to concentrate in the spleen, kidney,
liver, and gastrointestinal tract. Leukocytes also avidly
accumulate and store colchicine even after a single intravenous
injection. Since colchicine can accumulate in
cells against a concentration gradient, it is postulated
that an active transport process may be involved in its
cellular uptake. The drug is metabolized, primarily in
the liver, by deacetylation. Fecal excretion plays a major
role in colchicine elimination, since it and its metabolites
are readily secreted into the bile. Only about 15 to
30% of the drug is eliminated in the urine except in patients
with liver disease; urinary excretion is more important
in these individuals.
Pharmacokinetics
Colchicine is absorbed on oral administration, with peak plasma levels being attained within 0.5 to 2 hours after
dosing. Plasma protein binding is only 31%. It concentrates primarily in the intestinal tract, liver, kidney, and spleen
and is excreted primarily in the feces, with only 20% of an oral dose being excreted in the urine. It is retained in the
body for considerable periods of time, being detected in the urine and leukocytes for 9 to 10 days following a single
dose.
Pharmacology
The drug
can be given intravenously as well as orally, but care
must be exercised, since extravasated drug may result in
local sloughing of skin and subcutaneous tissues. Relief
of pain and inflammation usually occurs within 48
hours. Small doses of colchicine can be used during
asymptomatic periods to minimize the reappearance or
severity of acute attacks. It should be used with caution
in patients with preexisting compromised heart, kidney,
gastrointestinal tract, and liver disease.
Diarrhea, nausea, vomiting, and abdominal pain are
the major limiting side effects that ultimately determine
the tolerated dosage. These symptoms occur in approximately
80% of patients who take colchicine, especially in those taking high dosages. The hepatobiliary recycling
of colchicine and its antimitotic effect on cells that
are rapidly turning over, such as those of the intestinal
epithelium, account for its gastrointestinal toxicity.
Gastrointestinal symptoms generally intervene before
the appearance of more serious toxicity and thereby
provide a margin of safety in drug administration.
Ingestion of large doses of colchicine may be followed
by a burning sensation in the throat, bloody diarrhea,
shock, hematuria, oliguria, and central nervous system
(CNS) depression.
Anticancer Research
It is a natural toxic secondary metabolite, extracted from Colchicum genus plants. Itprevents gastric cancer by upregulating the dual specificity phosphatase 1 (DUSP1)gene. It is also reported to upregulate transforming growth factor beta 2 (TGF-β2)and A-kinase anchoring protein 12 (AKAP12) in hepatocellular carcinoma (Singhet al. 2016b).
Clinical Use
The major use of colchicine is as an antiinflammatory
agent in the treatment of acute gouty arthritis; it is not effective
in reducing inflammation in other disorders. It also
can be used to prevent attacks. Since colchicine is so rapidly
effective in relieving the acute symptoms of gout
(substantial improvement is achieved within hours), it
has been used as a diagnostic aid in this disorder.
Therapy with colchicine is usually begun at the first
sign of an attack and is continued until symptoms subside,
adverse gastrointestinal reactions appear, or a
maximum dose of 6 to 7 mg has been reached.
Synthesis
1. Organic solvent extraction method
According to the nature of colchicine and its analogs, ethanol, methanol and benzene are generally used as solvents for extraction, which is simple, low-cost and consumes less solvent, but the extraction rate
Veterinary Drugs and Treatments
In veterinary medicine, colchicine has been proposed as a treatment
in small animals for amyloidosis.
For colchicine to be effective,
however, it must be given early in the course of the disease and
it will be ineffective once renal failure has occurred. At the time of
writing, no conclusive evidence exists for its efficacy for this indication
in dogs.
Colchicine has also been proposed for treating chronic hepatic
fibrosis presumably by decreasing the formation and increasing the
breakdown of collagen.
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: possible increased risk of toxicity
with amiodarone.
Antibacterials: possible increased risk of toxicity
with azithromycin, clarithromycin, erythromycin and
telithromycin - suspend or reduce dose of colchicine,
avoid concomitant use in renal or hepatic failure.
Antifungals: possible increased risk of toxicity with
itraconazole and ketoconazole - suspend or reduce
dose of colchicine, avoid concomitant use in renal or
hepatic failure.
Antivirals: possible increased risk of toxicity with
atazanavir, indinavir, ritonavir and telaprevir
- suspend or reduce dose of colchicine, avoid
concomitant use in renal or hepatic failure.
Calcium-channel blockers: possible increased risk of
toxicity with diltiazem and verapamil - suspend or
reduce dose of colchicine, avoid concomitant use in
renal or hepatic failure.
Cardiac glycosides: possible increased risk of
myopathy with digoxin.
Ciclosporin: risk of myopathy or rhabdomyolysis,
also increased blood-ciclosporin concentrations
and nephrotoxicity - suspend or reduce dose of
colchicine, avoid concomitant use in renal or hepatic
failure.
Grapefruit juice: possible increased risk of toxicity.
Lipid-regulating drugs: possible increased risk of
myopathy with fibrates and statins.
Environmental Fate
Colchicine binds to tubulin and prevents its polymerization
into microtubules, subsequently disrupting microtubule function.
Consequently, it alters nuclear structure, intracellular
transport, and cytoplasmic motility, ultimately causing cell
death. Colchicine is a potent inhibitor of cellular mitosis.
Metabolism
Metabolism occurs primarily in the liver, with the major metabolite being the amine resulting from amide
hydrolysis.
Purification Methods
Commercial material contains up to 4% desmethylcolchicine. Purify colchicine by chromatography on alumina and eluting with CHCl3 [Ashley & Harris J Chem Soc 677 1944]. Alternatively, an acetone solution on alkali-free alumina has been used, and eluting with acetone [Nicholls & Tarbell J Am Chem Soc 75 1104 1953]. It crystallises as yellow needles from EtOAc or CHCl3 with solvent of crystallisation which can be removed at ~70o. It is soluble in Et2O (0.5%), *C6H6 (1%) and H2O (4%). It is sold as “Colgout” for the treatment of gout and binds to tubulin. [Schreiber et al. Helv Chim Acta 44 540 1961, Scott et al. Tetrahedron 21 3605 1965, van Tamelen et al. Tetrahedron 14 8 1961, Beilstein 14 IV 946.]
Toxicity evaluation
No information is currently available on breakdown in soil,
groundwater, or surface water. Colchicine alkaloids withstand
storage, drying, and boiling.
Ingestion is the most common route of both accidental and
intentional exposure to colchicine. It is available as an oral
tablet and solution for injection.
References
1) Merck 14:2471
