APLICATIONS OF COLCHICINE AS AN ARTICLE IN MEDICINE

By Babak Nami

INTRODUCTION
Colchicine is an alkaloid and toxic natural product as secondary metabolite, originally extracted from plants of the genus Colchicum (autumn crocus, Colchicum autumnale, also known as "meadow saffron") It is used to alleviate acute gout and to prevent acute attacks of familial Mediterranean fever (FMF). It is also being investigated for its use as an anti cancer drug. Colchicine is believed to interfere with cell division through itsdisruptive action on the mitotic spindle.

HISTORY
Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides in the first century CE. was first isolated in 1820 by the two French chemists P.S. Pelletier and J. Caventon. The precursor of colchicine Colchicum was described for treatment of rheumatism and swelling in the Ebers Papyrus, 1500 B.C.

HISTORY
Colchicum corm was used by ibn Sina Persian physician and other Islamic physicians, was recommended by Ambroise Pare in the sixteenth century, Cochicine appeared in the London Pharmacopoeia of 1618. In 1833 P.L. Geiger purified an active ingredient, which he named colchicine. Colchicum was brought to America by Benjamin Franklin.

NATURAL FUNCTION
Since chromosome segregation 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 gametes 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).

NATURAL FUNCTION
It is used to create seedless watermelons by colchicine's ability to induce polyploidy. It has to be applied to a growth point of the plant, such as an apical tip, shoot or sucker.

THE INHIBITION OF MITOSIS

Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. As a "mitotic poison" or spindle poison.

 Colchicine, colcemid, and inhibit polymerization by binding to tubulin and preventing its addition to the plus ends. The figure to the right shows this inhibition by colchicine (red). Vinblastine and vincristine aggregate tubulin and lead to microtubule depolymerization. Taxol stabilizes microtubules by binding to a polymer

Interference between colchicine binding and the straight conformation of tubulin in protofilaments. An subunit is positioned near a colchicine-bound subunit as across an intradimer longitudinal contact in a protofilament. The -tubulin subunit is prevented from occupying this position because of: (1) steric hindrance between colchicine and residues 101, 181 and GTP; and (2) colchicine forcing the T7 loop, H8 helix (for clarity, only side chains of two interfering residues71 and 251are presented) and the Lys 352 side chain to interfere with -tubulin.

DAMA-colchicine superimposed on electron-density maps. The 3.5 FobsFcalc omit map (cyan) is contoured at 3. The 4 FobsFcalc maps calculated with colchicine (red, contoured at 3) and with DAMA-colchicine but Fobs of a tubulincolchicine:RB3-SLD complex (green, contoured at -3.3) are also presented.

The colchicine site in the tubulincolchicine:RB3-SLD complex (bright colours: tubulin loops and secondary structure elements contacting colchicine)

COLCHICINE AS AN DRUG
It was used originally to treat rheumatic complaints especially gout and FMF. It was also prescribed for its cathartic and emetic effects. it can also be used as initial treatment for pericarditis and preventing recurrences of the condition. It is also being investigated for its use as an anti-cancer drug.

 On July 29, 2009 U.S. Food and Drug Administration (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.

ANTI-CANCER EFFECT
Colchicine inhibits cell division by prevention of microtubules formation. Availability of microtubules essential to mitosis. Cancer cells are significantly more vulnerable to colchicine poisoning than are normal cells. Therefore cancer cells desist in low dosage of Colchicine.

 colchicine also inhibits neutrophil motility and activity (the mechanism is unmanifested yet), leading to a net anti-inflammatory effect. Colchicine also inhibits the deposition of Uric acid (urat) crystals. Since the formation of such crystals is enhanced by a low PH in the tissues, it is surmised that colchicine raises the tissue pH by inhibiting the oxidation of glucose, thereby reducing the production of lactic acid in leukocytes. The inhibition of Uric acid crystals is a vital aspect of the mechanism of gout and FMF treatment.

ANTI-INFLAMMATORY EFFECT

Uric acid (C5H4N4O3) crystals in blood;(6500x)

RECENT RESULTS
According S. Bergmann, The anti-inammatory effect of colchicine may be mediated through changes at the transcriptional level. In neurons, axoplasmic transport is disrupted by colchicine. It is used as an anti-inflammatory agent for long-term treatment of Behets disease.

 The Australian biotechnology company Giaconda has developed a combination therapy to treat constipation-predominant irritable bowel syndrome which combines colchicine with the anti-inflammatory drug olsalazine.

SIDE EFFECTS
Side effects include gastrointestinal upset and neutropenia. High doses can also damage bone marrow and lead to anemia. Note that all of these side effects can result from hyperinhibition of mitosis.

Toxicity
Cochicine inhibit cell division, so it is a toxic for Eukaryotic cells in high dosage. Colchicine poisoning has been compared to arsenic poisoning. symptoms 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

 Hypovolemic shock due to extreme vascular damage and fluid loss through the GI tract, which may result in death. 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.

THANKS FOR ATTENTION