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PubMed2005

Colchicine for primary biliary cirrhosis: a Cochrane Hepato-Biliary Group systematic review of randomized clinical trials.

OBJECTIVES: Colchicine is used for patients with primary biliary cirrhosis due to its immunomodulatory and antifibrotic potential. The results from randomized clinical trials have, however, been inconsistent. We conducted a systematical review to evaluate the effect of colchicine for primary biliary cirrhosis. METHODS: We identified randomized clinical trials comparing colchicine with placebo/no intervention. We analyzed effects by fixed and random effects model. We investigated heterogeneity by subgroup and sensitivity analyses. RESULTS: We included 10 trials involving 631 patients, four of which were high-quality trials. No significant differences were detected between colchicine and placebo/no intervention regarding mortality (relative risk (RR), 1.21; 95% confidence interval (CI), 0.71-2.06), mortality or liver transplantation (RR = 1.00; 95% CI, 0.67-1.49), liver complications, liver biochemical variables, liver histology, or adverse events. Regarding mortality, an extreme case analysis favoring colchicine did not demonstrate beneficial effects of colchicine, whereas an extreme case analysis favoring placebo/no intervention demonstrated a detrimental effect of colchicine (RR = 2.28; 95% CI, 1.17-4.44). The number of patients without improvement of pruritus significantly decreased in the colchicine group (RR = 0.75; 95% CI, 0.65-0.87). However, this estimate was based on only 156 patients from three trials. CONCLUSIONS: There is insufficient evidence to support the use of colchicine for patients with primary biliary cirrhosis. As we are unable to exclude a risk of increased mortality, we recommend to use colchicine only in randomized clinical trials.

Colchicine↗

PubMed1967

The dissociation by colchicine of phagocytosis from increased oxygen consumption in human leukocytes.

The effect of colchicine on the uptake of oxygen by human leukocytes during phagocytosis of live streptococci or of killed staphylococci was compared with the effect of colchicine on phagocytosis per se, measured in a sensitive bacterial system. The increase in oxygen consumption that normally accompanies phagocytosis was consistently diminished in leukocytes incubated with colchicine in concentrations as low as 2.5 x 10(-6) mole per L (1 mug per ml), and this inhibition was dosage dependent. Yet there was no evidence of decreased phagocytosis with concentrations of colchicine as high as 2.5 x 10(-4) mole per L (100 mug per ml). Furthermore, with measurements at 20, 40, and 60 minutes, the rate of phagocytosis was comparable with and without colchicine.A clue to the dissociation between oxygen consumption and phagocytosis was found in rapidly dried preparations of the incubated leukocytes. Ingested bacteria were present in both control and colchicine-treated granulocytes. In addition, control cells showed normal loss of granules (lysosomal particles) and prominent cytoplasmic vacuoles (digestive vacuoles). Colchicine-treated cells, however, showed less such degranulation and vacuolization. Measurements of granule-associated acid phosphatase activity after phagocytosis support the morphologic observations of less degranulation in colchicine-treated leukocytes. The muted metabolic and morpholgic response to phagocytosis in colchicine-treated cells may be important for the anti-inflammatory effect of colchicine in acute gouty arthritis. Colchicine may also find wider use in defining structure-function dependencies in metabolically stimulated cells.

Colchicine↗

PubMed1996

Markedly altered colchicine kinetics in a fatal intoxication: examination of contributing factors.

1. Colchicine poisoning, which is relatively rare, is associated with significant morbidity and mortality. Whilst a new treatment modality, in the form of colchicine-specific Fab fragments is on the horizon, currently available therapy is largely supportive. 2. The elimination of colchicine occurs primarily by hepatic metabolism, following a first-order process, with significant enterohepatic circulation. Renal extraction is responsible for approximately 20% of colchicine elimination. 3. We report a case of colchicine intoxication, complicated by the presence of co-ingestants, in which serum colchicine concentrations remained quasi-constant over the 3 days of the patient's survival, consistent with marked alterations both in metabolism and excretion. The initial presentation was relatively benign but the subsequent course was one of severe colchicine poisoning, resulting in death. 4. Severe colchicine toxicity appears to have resulted in a vicious cycle of progressive organ dysfunction and impaired elimination. 5. Josamycin, one of the co-ingestants and an inhibitor of P-glycoprotein, the membrane pump responsible for multidrug resistance, may have played a significant role in impeding the cellular and biliary elimination of colchicine. Co-ingested opioid and anticholinergic compounds may have altered colchicine absorption and gastrointestinal transit. 6. This case serves as a reminder of the need for attention to co-ingested drugs, to early aggressive therapy, and if available, to consideration of immunotherapy.

Adult↗

PubMed2004

Colchicine myotoxicity: case reports and literature review.

Two of our patients experienced myotoxicity associated with colchicine administration. The first was a 54-year-old woman who was receiving dialysis and came to the emergency department with progressive generalized weakness and vomiting. She recently had taken colchicine for the treatment of gout. Physical examination revealed proximal muscle weakness and tenderness on palpation. Her creatine kinase (CK), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were elevated at 7185, 563, and 541 U/L, respectively. Drug-induced myopathy was suspected and colchicine was discontinued. The patient was discharged after symptom resolution 1 week later. The second patient was an 83-year-old woman with chronic renal insufficiency who came to the hospital with anorexia, diarrhea, and inability to get out of bed due to progressive weakness. Her colchicine dosage recently had been increased for gout management. Physical examination revealed generalized muscle weakness and tenderness on palpation. Her CK, ALT, and AST levels were elevated at 1797, 147, and 172 U/L, respectively. Electromyographic results were consistent with colchicine myopathy. The patient was discharged with minimal residual muscle weakness 1 week after discontinuation of colchicine. A literature search identified 82 documented cases of colchicine-induced myotoxicity. Most patients had a history of proximal weakness and pain with elevated CK, ALT, and AST levels. Onset of symptoms generally occurred days to weeks after initial administration of colchicine at the usual dosage in patients with renal impairment or a change in underlying disease state in those receiving long-term therapy. Muscle toxicity was not necessarily accompanied by gastrointestinal symptoms. Concomitantly administered drugs often were cyclosporine or corticosteroids. Diagnosis may be confirmed by electromyography or muscle biopsy. Colchicine-induced myotoxicity is a rare adverse effect but is well described in the literature. Clinicians should recognize that renal impairment is the primary risk factor for development of colchicine-induced myotoxicity, and that dosage adjustment or alternative therapy may be required.

Aged↗

PubMed2005

Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update.

Familial Mediterranean Fever (FMF), an autosomal recessive disorder, is characterised by recurrent attacks of fever and serositis, lasting 24-72 hours. Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. Colchicine, an alkaloid neutral, is absorbed in the jejunum and ileum. It metabolised by liver and only small amounts are recovered unchanged in the urine. Really plasma half-life is prolonged in patients with liver or renal failure. Colchicine is able to prevent activation of neutrophils, binding beta-tubulin and making beta-tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover its mode of action includes modulation of chemokines, prostanoids production, inhibition of neutrophil and endothelial cell adhesion molecules. The minimal daily dose in adults is 1.0 mg/die, but in children there is not a definite dose. Since in vitro high dosages of colchicine stop mitosis, this drug might interfere with male and female fertility and with children growth, but, according to current guidelines and because of rare side effects of the drug, FMF patients are recommended to take colchicine. Since colchicine treatment is often complicated by frequent gastrointestinal side effects, by our experience, in order to improve colchicine tolerance we recommend: lactose-free diet and treatment of intestinal bacterial overgrowth and/or Hp-infection, assessed by breath tests. Since our data showed that 10-15% of FMF patients seem are non-responders or intolerant to colchicine, today we are working in the design of colchicine analogues which may have lesser toxicities and a larger therapeutic window.

Adult↗

PubMed1981

Colchicine and insulin secretion in man.

The present study is aimed at investigating the effect of acute and chronic colchicine administration on insulin secretion in humans. Acute insulin response to glucose (0.33 g/kg) was significantly decreased by colchicine (3 mg i.v.). In fact, this response (mean change 2-10 min insulin) was 44 +/- 8 microunits/ml before and 32 +/- 6 microunits/ml after colchicine administration (P less than 0.01). As a consequence of this, glucose disappearance rates were reduced (P less than 0.05). Infusion of lysine acetylsalicylate (LAS), an inhibitor of endogenous PG synthesis, completely reversed the inhibitory effect of colchicine upon insulin secretion and also augmented acute insulin response to glucose (response before colchicine + LAS = 45 +/- 8 microunits/ml; response after colchicine + LAS = 51 +/- 9 microunits/ml, P less than 0.05). This effect was associated with an increase in glucose disappearance rates (P less than 0.05). The 10-day treatment with colchicine (2 mg daily) caused a significant suppression of insulin secretion induced by oral glucose (100 g) and significantly increased the plasma glucose concentrations following the test (P less than 0.05). These findings demonstrate that (1) both acute and chronic colchicine administration inhibit glucose-induced insulin secretion and deteriorate glucose tolerance in humans, and (2) LAS completely reverses these negative effects of colchicine. An increased synthesis of endogenous PGE, which are known to inhibit insulin secretion in humans, might account for the inhibiting effect of colchicine on insulin secretion.

Adult↗

PubMed1991

Colchicine-induced ciliated vacuoles in tracheal mucosa.

In most cells the microtubules are destroyed and disappear after administration of colchicine in concentrations as low as 10(-6) M; colchicine inhibits the polymerization of tubulin and destroys the microtubules. Ciliary microtubules have resistance to colchicine but can, on the other hand, be destroyed by high concentrations of colchicine. In this study, we treated rabbits with considerably high concentrations (10 or 20 mg/100 g body weight) of colchicine for four successive weeks and examined the effects on the tracheal cilia. Abdominal administration of colchicine did not affect the morphology and structure of the cilia projecting on the cellular surface. However, ciliated vacuoles were observed in tracheal epithelial cells of rabbits treated with colchicine. The occurrence of such ciliated vacuoles depended on the dosage of colchicine: 2.4 +/- 0.4 per 100 microns epithelial length when treated with 10 mg/100 g body weight of colchicine, and 3.8 +/- 0.3 per 100 microns epithelial length when treated with 20 mg/100 g body weight. Some cilia present in ciliated vacuoles were pathological. In conclusion, a considerably high dosage of colchicine can inhibit ciliary microtubules during ciliogenesis, resulting in ciliated vacuoles.

Animals↗

PubMed1975

The role of microtubules in chick blastoderm expansion--a quantitative study using colchicine.

Since their discovery, cytoplasmic microtubules have been much studied in the context of cell movement and cell shape change. Much of the work has used drugs, particularly colchicine and its relatives, which break down microtubules- the so-called anti-tubulins. Colchicine and its relatives, which break down microtubules- the so-called anti-tubulins. Colchicine inhibits the orientated movements of many cell types in vitro, and disrupts cell shape change in several morphogenetic situations. The investigatiion reported here used chick blastoderm expansion in New culture in an attempt to quantify the colchicine effect on orientated cell movement. However, although colchicine could halt blastoderm expansion entirely, a simple interpretation was not possible. (1) Colchicine at concentrations capable of blocking mitosis, and of disrupting all or most of the cytoplasmic microtubules of the cells studied, inhibited blastoderm expansion, often resulting in an overall retraction of the cell sheet. (2) Though blastoderm expansion does normally involve considerable cell proliferation, the colchicine effect could not be ascribed to a block on cell division since aminopterin, which stops cell division without affecting microtubules, did not inhibit expansion. (3) Blastoderm expansion is effected by the locomotion of a specialized band of edge cells at the blastoderm periphery. These are the only cells normally attached to the vitelline membrane - the substrate for expansion. When most of the blastoderm was excised, leaving the band of edge cells, and the cultures then treated with colchicine, expansion occurred normally. The colchicine effect on blastoderm expansion could not therefore be ascribed to a direct effect on the edge cells. (4) An alternative site of action of the drug is the remaining cells of the blastoderm. These normally become progressively flatter as expansion proceeds. If flattening in these cells is even partially dependent on their cytoplasmic microtubules, disruption of these microtubules might result in the inherent contractility of the cells resisting and eventually halting edge cell migration. That cell shape in these cells is dependent on microtubules was demonstrated by treating flat blastoderm fragments with colchicine. On incubation, the area occupied by these fragments decreased by 25-30% more than controls. The significance of these results in the general context of orientated cell movements and cell shape determination is discussed, with particular emphasis on the analogous system of Fundulus epiboly.

Aminopterin↗

PubMed1992

Modulation of platelet-derived growth factor B mRNA abundance in macrophages by colchicine and dibutyryl-cAMP.

Macrophage production of growth factors for fibroblasts, in particular platelet-derived growth factor B [PDGF(B)] and transforming growth factor-beta (TGF-beta), is thought to be central to the pathogenesis of pulmonary fibrosis. In a search for anti-inflammatory agents that might prevent this process, we asked whether colchicine might modulate the abundance of PDGF(B) and TGF-beta mRNA, as well as the mRNA of early growth response gene 2 (EGR2), in human macrophages. Colchicine caused a dose- and time-dependent increase in PDGF(B), but not TGF-beta or EGR2, mRNA in human macrophages derived from culture of peripheral blood monocytes. Similarly, colchicine caused an increase in PDGF(B) mRNA in human alveolar macrophages obtained from normal volunteers. Colchicine also caused an increase in PDGF(B) protein production by macrophages, as determined by enzyme-linked immunosorbent assay. Interferon-gamma further increased the PDGF(B) mRNA abundance in human alveolar but not monocyte-derived macrophages. The effect of coincubation with dibutyryl-cAMP (dBcAMP) was assessed in an attempt to prevent the colchicine-induced increase in PDGF(B) mRNA. dBcAMP alone resulted in no increase in PDGF(B) mRNA or alteration in TGF-beta mRNA but resulted in a reduction in EGR2 mRNA. When added with colchicine, dBcAMP completely abrogated the colchicine-induced increase in PDGF(B) mRNA but had little effect on TGF-beta mRNA. These data, showing that colchicine increased macrophage PDGF(B) mRNA in human macrophages and that this was prevented by coincubation with dBcAMP, lead us to speculate that colchicine may not be helpful in preventing the contribution of macrophage PDGF(B) gene activation to the pathogenesis of lung fibrosis. However, this effect of colchicine may be prevented by increasing intracellular cAMP in macrophages.

Bucladesine↗

PubMed2004

Severe respiratory muscle weakness related to long-term colchicine therapy.

We report a case of colchicine-induced myopathy, in which the initial presenting and predominant clinical feature was respiratory muscle dysfunction; there was also chronic renal failure and electromyographically-measured myopathy. Discontinuation of colchicine led to marked improvement. Colchicine discontinuation was the only therapy performed (other medications were unchanged), and within 3 weeks the patient had regained motor function and resumed daily activities. Myopathy from primary biliary cirrhosis was ruled out. In contrast to acute colchicine intoxication, chronic colchicine toxicity is related to prolonged use rather than colchicine serum level, so colchicine serum level was not measured and did not affect the decision to discontinue colchicine. Although the diagnosis was not confirmed by muscle biopsy, we believe the typical presentation and the rapid improvement after withdrawing colchicine confirm the diagnosis. We conclude that long-term colchicine therapy, especially in the setting of chronic renal failure, can produce symptomatic respiratory muscle weakness.

Colchicine↗

PubMed2003

Influence of colchicine on pulmonary silicotic fibrogenesis in rats.

With an aim to evaluate the antifibrotic action of colchicine in experimental model of pulmonary silicosis, the effect of colchicine on developing and developed pulmonary silicosis induced by quartz was studied in rats in vivo and on alveolar macrophages exposed to quartz particulates in vitro. A progressive increase in wet and dry weight of lungs exposed to quartz dust alone, and quartz dust and colchicine injected orally was investigated. An increase in collagen contents, with lapse in time, in animals exposed intratracheally to quartz dust, or exposed similarly to quartz dust but receiving colchicine simultaneously through oral route was observed. A blindfold evaluation of histological sections of lungs of silicotic animals with or without colchicine administration during development of lesions did not reveal any difference between two groups of silicotic rats. Administration of colchicine for 4 weeks after the lesions were developed neither inhibited nor retarded the laying down of collagen. The studies were extended to investigate the effect of colchicine on quartz-induced alveolar macrophage cytotoxicity. The presence of varying concentrations of colchicine in the culture medium did not significantly alter cytotoxic potential of quartz. The results reveal that colchicine administration during the development of and on developed silicosis does not significantly alter pathogenesis of silicotic lesions. At the cellular level colchicine does not modulate quartz-induced alveolar macrophage cytotoxicity, believed to be a significant event for the onset of pulmonary silicotic fibrogenesis.

Animals↗

PubMed1990

N-acetylcolchinol O-methyl ether and thiocolchicine, potent analogs of colchicine modified in the C ring. Evaluation of the mechanistic basis for their enhanced biological properties.

Two colchicine analogs with modifications only in the C ring are better inhibitors than colchicine of cell growth and tubulin polymerization. Radiolabeled thiocolchicine (with a thiomethyl instead of a methoxy group at position C-10) and N-acetylcolchinol O-methyl ether (NCME) (with a methoxy-substituted benzenoid instead of the methoxy-substituted tropone C ring) were prepared for comparison with colchicine. Scatchard analysis indicated a single binding site with KD values of 1.0-2.3 microM. Thiocolchicine was bound 2-4 times as rapidly as colchicine, but the activation energies of the reactions were nearly identical (18 kcal/mol for colchicine, 20 kcal/mol for thiocolchicine). NCME bound to tubulin in a biphasic reaction. The faster phase was 60 times as fast as colchicine binding at 37 degrees C, and a substantial reaction occurred at 0 degrees C. The rate of the faster phase of NCME binding changed relatively little as a function of temperature, so the activation energy was only 7.0 kcal/mol. Dissociation reactions were also evaluated, and at 37 degrees C the half-lives of the tubulin-drug complexes were 11 min for NCME, 24 h for thiocolchicine, and 27 h for colchicine. Relative dissociation rates as a function of temperature varied little among the drug complexes. Activation energies for the dissociation reactions were 30 kcal/mol for thiocolchicine, 27 kcal/mol for NCME, and 24 kcal/mol for colchicine. Comparison of the activation energies of association and dissociation yielded free energies for the binding reactions of -20 kcal/mol for NCME, -10 kcal/mol for thiocolchicine, and -6 kcal/mol for colchicine. The greater effectiveness of NCME and thiocolchicine as compared with colchicine in biological assays probably derives from their more rapid binding to tubulin and the lower free energies of their binding reactions.

Animals↗

PubMed1988

Colchicine does not interfere with the antiphosphaturic effect of 25(OH) vitamin D3 in the rat.

The effect of colchicine pretreatment on the antiphosphaturic action of 25(OH)vitamin D3 (25[OH]D3) was examined in parathyroidectomized (PTX), parathyroid-hormone (PTH)-infused rats by acute clearance studies. The following groups were studied: group 1, colchicine-pretreated PTX rats; group 2, colchicine-pretreated PTX rats receiving PTH infusion; group 3, colchicine-pretreated PTH-infused PTX rats receiving intravenous 25(OH)D3 with pretreated PTH-infused PTX rats serving as controls. The effect of 25(OH)D3 on PTH-activated renal adenylate cyclase [AC] from colchicine-pretreated rats was studied in vitro. In group 1, fractional excretion of phosphate (Cp/CIn) after colchicine was 0.102 +/- 0.011 vs. 0.029 +/- 0.005 in controls (p less than 0.001). In group 2, PTH increased Cp/CIn from 0.074 +/- 0.026 to 0.184 +/- 0.028 (p less than 0.05) in colchicine-pretreated animals and from 0.018 +/- 0.006 to 0.213 +/- 0.034 in controls (p less than 0.0025). In group 3, 25(OH)D3 decreased Cp/CIn from 0.344 +/- 0.022 to 0.235 +/- 0.026 (p less than 0.005) and UcAMP from 103.7 +/- 12.4 to 69.0 +/- 9.6 (p less than 0.025). In vitro PTH activation of AC was blunted in colchicine-pretreated rats; however, the response to 25(OH)D3 was intact. Histological changes compatible with microtubule disruption were found in proximal tubules of kidneys from colchicine-pretreated rats. These results show that colchicine alters the response to PTH but it does not affect the antiphosphaturic action of 25(OH)D3, suggesting that this action is not mediated via cytoplasmic microtubules.

Adenylyl Cyclases↗

PubMed1981

Comparison of mitostatic effect, cell uptake and tubulin-binding activity on colchicine and colcemid.

Mitostatic action, cellular uptake and the binding of colchicine and colcemid to tubulin were compared. It was shown that mitostatic action of low doses of colchicine developed only after 24 h incubation of the drug with mouse L fibroblasts, while the colcemid-induced block of mitosis was evident after 2 h incubation. The initial rate of uptake was about 10 times greater for colcemid than for colchicine. Cellular uptake of the drugs reached an equilibrium after 2 and 15-18 h incubation for colcemid and colchicine, respectively, and the plateau values were identical. The kinetics of colchicine and colcemid binding to bovine brain tubulin was studied by the DEAE-filter binding assay. Colcemid binds to tubulin much faster than does colchicine. The rate of colcemid efflux from L cells is much higher than that of colchicine. According to the efflux data, colcemid dissociates readily from a complex with tubulin (t1/2 = 10 min), while the colchicine-tubulin complex is stable for at least 1 h. These results are consistent with previously published data (Frankel, F.R. (1976) Proc. Natl. Acad. Sci. U.S.A. 72, 2798-2802), which showed that colcemid action on cells is more reversible than that of colchicine. We suggest that differences between colchicine and colcemid in the rate of mitostatic action and its reversibility are determined by the differences in parameters of tubulin binding.

Animals↗

PubMed1975

Colchicine uptake and binding by human platelets.

The uptake and binding of antimitotic alkaloid colchicine has been demonstrated in washed preparations of human pletelets. A silicone oil technique was adapted so that both uptake and binding of 14C-colchicine were examined in the same platelet preparations. The time dependence and amount of colchicine taken up and bound by different pletelet preparations during a 90 to 120 min incubation period were highly reproducible. Both colchicine uptake and binding by intact platelets, and colchicine binding by preparations of lysed platelets were specific and temperature dependent. Colchicine uptake was slowly reversible. Magnesium and GTP enhanced colchicine binding by lysed platelet preparations but calcium decreased binding. exposure of platelets to either cold (4 degrees C) or to thrombin, which disrupt platelet microtubules, produced significant increases in colchicine uptake and binding. The thrombin effect was maximal at 37 degrees C and resulted in a greater increase in uptake and binding than that produced by either cold treatment alone or, by cold treatment followed by incubation with thrombin at 37 degrees C. The amount of increase in uptake and binding produced by thrombin was independent of both thrombin (1--5 Units/10(9) platelets) and colchicine concentrations (1--50 X 10(-6) M). It is postulated that thrombin may initiate the formation, or make available, colchicine binding sites (microtubule subunits) within platelets.

Blood Platelets↗

PubMed1993

Effects of colchicine on pelvic adhesions associated with the intrauterine inoculation of Neisseria gonorrhoeae in rabbits.

OBJECTIVE: To determine whether colchicine, an anti-inflammatory drug, is effective in reducing adhesion formation in a rabbit model in which pelvic inflammation was produced by injection of a suspension of Neisseria gonorrhoeae into the uterine horn. METHODS: Following inoculation, the rabbits were divided into four groups of 11 animals each. The control group received 1 mL saline intramuscularly (IM) for 14 days. Another group received one 100-mg dose of ceftriaxone IM 2-4 hours after inoculation. The third group received one 100-mg dose of ceftriaxone IM 2-4 hours after inoculation and 1 mg colchicine IM daily for 14 days. The fourth group received 1 mg colchicine IM daily for 14 days. The day after the last injection of colchicine, the rabbits were sacrificed and the abdominal cavities were explored to determine the number and grade of adhesions. RESULTS: The incidence of adhesions in the control group was similar to that in the antibiotic-treated group, suggesting that antibiotics do not prevent adhesions in this model. Similarly, the incidence of adhesions in the colchicine and antibiotic group was not different from that in the group receiving colchicine alone. However, the colchicine-treated groups had significantly fewer adhesions than the groups not treated with colchicine (P < .0005). CONCLUSIONS: In this model, antibiotics alone did not prevent the formation of adhesions. Colchicine, alone or in combination with antibiotics, was effective in preventing bacteria-induced pelvic adhesions. Therefore, colchicine may offer a novel approach to the prevention of adhesions associated with pelvic inflammatory disease in women.

Animals↗

PubMed1998

Colchicine is a competitive antagonist at human recombinant gamma-aminobutyric acidA receptors.

Colchicine is an alkaloid that is used clinically in the treatment of arthritic gout. This potent microtubule disrupting agent has also been used extensively as an experimental tool in studies characterizing the role of the cytoskeleton in a variety of cellular processes. Colchicine has also been used as a selective neurotoxin and in animal models of Alzheimer's disease and epilepsy. Although the mechanism(s) mediating the neurotoxic actions of colchicine have not been established, most studies have attributed these effects to its microtubule depolymerizing actions. Here we report another central nervous system action of colchicine, competitive antagonism of gamma-aminobutyric acid (GABA)A receptor function. By use of a rapid drug perfusion system, colchicine (10-1000 microM) significantly inhibited GABA currents recorded from L(tk-) cells stably transfected with human alpha 1 beta 2 gamma 2L GABAA receptor subunits. The inhibition was rapid and reversible, with 100 microM colchicine shifting the GABA EC50 from 2.5 to 5.1 microM with no effect on currents evoked by saturating concentrations of GABA. Colchicine also significantly inhibited binding of the competitive GABAA receptor antagonist [3H]SR-95531. Other microtubule disrupting agents (10 microM vinblastine, 10 micrograms/ml nocodazole, 1 microM taxol) had no acute effects on GABA currents, nor did the inactive analog gamma-lumicolchicine (100 microM). Moreover, pretreating cells with colchicine, vinblastine, nocodazole or taxol for 1 to 4 hr did not occlude the acute inhibitory action of colchicine. We conclude that, in addition to its well characterized effects on microtubule assembly, colchicine can also inhibit GABAA receptor function through a direct interaction with the receptor/ion channel complex.

Animals↗

PubMed1965

ON THE ACTION OF COLCHICINE, THE MELANOCYTE MODEL.

The effect of colchicine was studied on the rapid, reversible darkening of frog skin under the influence of melanocyte-stimulating hormone (MSH). Darkening is due to dispersion of melanin granules in melanocytes and is thought to be accompanied by a gel-to-sol cytoplasmic transformation. After subsequent washing, the skin lightens, with aggregation of melanin granules and cytoplasmic gelation. Preincubation of skin with colchicine had the following effects: 1. Darkening induced by MSH was increased in comparison to control skins, and on removal of MSH, lightening was inhibited. Inhibition was a function of both concentration (1 x 10(-5) to 9 x 10(-5)M) and exposure time (2 to 30 minutes). Once established, inhibition was maintained throughout the remainder of the experiment. 2. The same effects were noted (a) when darkening was effected by agents other than MSH (ATP) 0.9 x 10(-3)M; caffeine, 5.2 x 10(-3)M; ethyl acetate, 0.8 x 10(-2)M), and (b) when lightening was effected by addition of chemical agents (melatonin, 4.3 x 10(-10)M; hydrocortisone, 1 x 10(-3)M; norepinephrine, 1 x 10(-3)M), instead of by washing. 3. Colchicine alone produced a gradual, irreversible, dosage-dependent darkening over several hours. This darkening was inhibited by melatonin, 4.3 x 10(-10)M. The melanocyte model is used to construct a general theory of colchicine action on living cells, an action resulting in decreased protoplasmic viscosity. In this formulation colchicine lowers the potential limit of protoplasmic gelation, and does it rapidly, reversibly, in low concentration, in a dosage-dependent manner, and without killing the cell. The theory allows interpretation of "synergism" and "antagonism" to colchicine by other substances. It suggests a tentative approach to the understanding of colchicine action in acute gouty arthritis, where interference with ameboid activities of polymorphonuclear leukocytes is one possible aspect of the anti-inflammatory effect of colchicine. Finally, the colchicine-treated melanocyte is viewed as a good, live physical model that can be used to elucidate some fundamental biological properties.

Acetates↗