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Jumat, 23 Januari 2009

Pharmacology of Colchicine

Colchicine, a water-soluble alkaloid found in the autumn crocus, blocks or suppresses cell division by inhibiting mitosis, the division of a cell's nucleus. Specifically, it inhibits the development of spindles as the nuclei are dividing. Normally, the cell would use its spindle fibers to line up its chromosomes, make a copy of them, and divide into two new cells with each daughter cell having a single set of chromosomes. With colchicine present, the spindle fibers don't form, and so the cell can't move its chromosomes around. The cell may end up copying some or all of the chromosomes anyway, but can't parcel them out into new cells, and so it never divides.
Because
cancer cells divide much more rapidly than normal cells, cancers are more susceptible to being poisoned by mitotic inhibitors such as colchicine, paclitaxel, and the Vinca alkaloids.
However, colchicine has proven to have a fairly narrow range of effectiveness as a chemotherapy agent, so its only FDA-approved use is to treat gout (it is one of the active ingredients of ColBenemid, anti-gout tablets marketed by Merck & Co.), though it is also occasionally used in veterinary medicine to treat cancers in some animals. It is also used as an antimitotic agent in cancer research involving
cell cultures.
Gout is an illness caused by faulty uric acid
metabolism in which excess uric acid is turned into crystals of sodium urate, which are then deposited in the joints (most often in the big toe), causing inflammation and pain. Researchers aren't sure exactly how colchicine works against gout, but it does seem to reduce the frequency of severe attacks and relieves residual pain.
As far as side effects go, colchicine can cause a temporary reduction in the number of
leukocytes (white blood cells) in the bloodstream; afterward, the leukocyte count can rebound to abnormally high levels. Colchicine also causes teratogenic birth defects in lab animals, and so pregnant women with gout should not use colchicine-containing drugs.
Colchicine poisoning resembles arsenic poisoning; the symptoms (which, because it is a mitotic poison, occur 2 to 5 hours after the toxic dose has been ingested) include burning in the mouth and throat, diarrhea, stomach pain, vomiting, and kidney failure. Death from respiratory failure often follows. A specific antidote doesn't exist, so treatment typically involves giving the victim
activated charcoal or pumping the stomach.
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