Pharmacological effects
Anti-gout effect
Colchicine (Col) is the only anti-inflammatory agent effective against gouty arthritis, especially acute for acute attacks of gout
The therapeutic effect is also an effective preventive medicine. Col is selective for acute gouty arthritis and only occasionally effective for other arthritis. Col is not an analgesic and is not effective for other types of pain. However, Col has an acute analgesic effect on acute and chronic intervertebral disc syndrome. The intravenous injection of Coilmg relieves pain, and the symptoms and signs improve rapidly. The mechanism of analgesia is not fully understood. Col does not affect the renal excretion of uric acid, nor does it affect the blood concentration of uric acid. Col binds to tubulin, hinders the function of spindles in mitosis and causes depolymerization and disappearance of fibrillar microtubules in granulocytes and other mobile cells. This effect is obviously the basis of Col's effective action, that is, it inhibits the migration of granulocytes to the inflamed area and reduces granulocyte metabolism and phagocytic activity. This action reduces the release of precursors of lactic acid and enzymes that cause inflammation that occur in phagocytosis, breaking the cycle of inflammatory responses. Neutrophils in contact with urate uptake urate and produce a glycoprotein, which may be a causative agent of acute gout arthritis. Injecting it into the joint can cause significant arthritis and infusion of urine. There was no difference in histology between crystals of acid salts. Col prevents white blood cells from producing this glycoprotein. 2. Anti-inflammatory effects: Col can significantly inhibit carrageenan-induced inflammatory edema, inhibit the secretion of histamine in mast cells, increase the level of cAMP in leukocytes, inhibit the release of lyase from polynuclear leukocytes in inflammation, and inhibit polynuclear leukocytes. The chemotaxis of mononuclear cells inhibits the synthesis of prostaglandins and leukotrienes and decreases the permeability of blood vessels, thereby facilitating the reduction of tissue inflammatory responses, reducing tissue edema, and reducing the stimulation of tissue by inflammatory mediators.
Anti-tumor effect
Col and its derivatives, colchicine amide (derived from the hydrolysis of Col with ammonium hydroxide, Colchicineamide) have inhibitory effects on a variety of animal transplantable tumors. The anti-tumor effect of colchicine amide is obvious, such as the inhibition rate of mouse sarcoma S180, S37 and liver cancer is approximately 70%, and the inhibition rate of 256 (W256) of rat vascular sarcoma is approximately 60%. The tumor inhibition rate is high with colchicine amide. Its anti-tumor spectrum is broader than that of Col, while its toxicity is low and the safety range is relatively large. The therapeutic index is 1.75 cu for Col. Their anti-tumor mechanism is due to their specific cell mitotic metaphase (M phase) blockers. Col has a high affinity with tubulin, forming a dimer between the two, making the microtubules unable to perform assembly functions, preventing the formation of spindles, preventing the chromosomes from moving to the poles, eventually conglomerating and stopping cell division in the medium term. Subsequent changes in the structure of the nucleus result in malformation and death of the cells. The more vigorous the division and the higher the metabolic rate, the cells are most susceptible to Col attacks. High concentrations can completely prevent mitosis, but when the spindle has formed, it no longer affects its division. Col also selectively blocks mitosis in normal cells.
Suppresses scar proliferation
The compound colchicine ion introduction method has obvious preventive and therapeutic effects on human skin scar proliferation. Through transmission electron microscopy, the mechanism of action of colchicine is mainly to destroy the microtubule system of the cell and interfere with excretion of collagen protein by fibroblasts, which hinders the formation of collagen fibers. Electron microscopy revealed that some fibroblasts had mitochondrial swelling, enlarged perinuclear space and rough endoplasmic reticulum, and mesangial changes of cytoplasmic membrane components. This was the toxicity of colchicine on fibroblasts. The increase in the number of autologous lysosomes in the cells suggests that the pre-collagen accumulated in the cells enters the lysosomal system through autophagy and is digested and degraded by enzymes in the lysosome.
Prevent adhesion formation
The pathological model of sciatic nerve injury in rabbits and the model of intestinal adhesions were surgically performed to observe the effects of colchicine. The results showed that colchicine was intramuscularly injected at 125 μg/kg daily for 4 weeks, and the tissues around the nerve were observed. Adhesion and fibrosis have obvious inhibitory effects. Rabbits were injected intraperitoneally with 30 mg/L. The colchicine solution was used at a dose of 1 mg/kg. The laparotomy was performed 10-15 days after surgery. The number of adhesions, the degree of adhesion, and the adhesion area were recorded. The adhesion tissue was observed by electron microscopy. The results showed that the colitis formed by the colchicine group. Brittle, loose and easy to separate. Capillary hyperplasia is reduced and mainly fibroblasts are present. Electron microscopy revealed that there were clusters of medium electron density particles in the fibroblasts, and mitochondrial degeneration. The area of ​​intraperitoneal adhesions was significantly reduced, but there was no significant decrease in the number of adhesions, suggesting that colchicine has a positive preventive effect on intra-abdominal adhesions in rabbits, and the level of 1mg/kg does not cause significant changes in the functional status of rabbits, but It is also suggested that the above dose is not the maximum effect of anti-adhesion tissue, and its anti-adhesion mode of administration should be within 2-7 days after surgery.
Liver protection
Mice were injected intraperitoneally with olive oil solutions of two concentrations (12.5%, 25%) of carbon tetrachloride (CCI4) to cause a model of toxic hepatic necrosis. Some mice were given testosterone propionate or estradiol valerate subcutaneously. Injection, see testosterone has no effect on the survival rate of male and female rats, but can improve colchicine treatment of female rats, showing colchicine (0.5μg/, gavage, once daily, a total of 14 times) on male rats The therapeutic effect is better than female mice. Estradiol can promote the death of all male mice. After adding colchicine, half of the males survived. There was a significant difference, and the liver pathological changes of survivors were also lighter, suggesting a protective effect of liver. The use of estradiol alone can cause female mice to counteract the toxic effects of higher doses of carbon tetrachloride, which is significantly different from that of colchicine alone.
Other effects
The subcutaneous injection of Col (3 mg/kg) into rabbits can decrease the total number of white blood cells for 1 hour. After 2 to 6 hours, the white blood cells increase significantly and reach a peak within 10-24 hours. 5 times; After intravenous injection, the peripheral blood eosinophilic leukocytes can be reduced by 70%, after the removal of the pituitary gland by 50%, in the leukocyte decline phase, blood coagulation accelerated, but with the increase in the number of white blood cells, blood coagulation also delayed. Col can selectively inhibit respiratory (spleen, thymus) respiration 24 hours after injection in normal rats. After removal of the adrenal gland, this effect is reduced, suggesting that this effect may be related to the drug affecting adrenocortical function. Col can cause hemorrhage in transplanted tumors when approaching toxic doses; it can also reduce the content of ascorbic acid in anti-tumor tissues; at the same time, it can also reduce the content of ascorbic acid in liver and small intestine of rats and mice, but it does not affect liver metabolism. In addition, Col can also enhance or prolong the effect of hypnotic drugs, increase the sensitivity of central inhibitors, and inhibit the respiratory center; increase the response of sympathomimetic drugs, and stimulate the center of blood vessels to increase Blood Pressure . It has stimulatory effects on the gastrointestinal mucosa and can cause congestion and even hemorrhagic gastroenteritis.
In vivo process
Normal mice were injected subcutaneously with 14C-COI or colchicine, and their distribution in vivo was observed after 4 hours, mainly in the spleen, which was 40% of the dose, followed by the kidney and small intestine, and the liver was the least, while the blood and brain were , muscles and heart are not radioactive. Colchicine has a higher content of tumors, while Col has less. Col is excreted slowly in the body and remains in the body at about 50% after 16 hours of intravenous injection. Col is mainly excreted in the bile and small intestine in rats, dogs, and cats, and excreted less in the urine. Colchicine excreted quickly via urine and there was no significant accumulation. Col can be excreted from the respiratory tract and the 14CO2 emitted within 24 hours is about 5%-23% of the total amount of the original drug. Colchicine failed to detect radioactivity in breath. And radioactive substances discharged from the urine have the prototype and its decomposition products.
After oral administration of Col, it is rapidly absorbed. Peak plasma concentrations occur 0.5-2 hours after administration. Col and most of its metabolites are secreted into the intestine via the bile and intestines. For this reason, coupled with the rapid renewal of the intestinal epithelium, it is more susceptible to the effects of COI. This explains why intestinal symptoms are more prominent in Chl poisoning. After a single intravenous injection of Col, the drug can be detected in leukocytes and urine for at least 9 days. Most of the Col is excreted from the feces, and about 10% to 20% is excreted in the urine. In patients with liver diseases, the intake and elimination of the drug by the liver is reduced, and the fraction excreted from the urine is increased.
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