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PubMed2004

Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis.

OBJECTIVE: The use of colchicine to prevent acute gout flares during initiation of allopurinol therapy is widely practiced despite lack of proven benefit. We investigated if colchicine administration during initiation of allopurinol for chronic gouty arthritis reduces the frequency and/or severity of acute gout flares. METHODS: Patients starting allopurinol for crystal-proven chronic gouty arthritis were randomized to receive colchicine 0.6 mg po bid or placebo in a randomized, prospective, double blind, placebo controlled trial. Subjects were followed for evidence of acute gout flares and remained on study drug for 3 months beyond attaining a serum urate concentration < 6.5 mg/dl. Treatment arms were analyzed regarding frequency of flares, likelihood of any flare or multiple flares, severity of flares on the visual analog scale (VAS), and length of flares in days. RESULTS: Forty-three subjects were studied. Subjects treated with colchicine experienced fewer total flares (0.52 vs 2.91, p = 0.008), fewer flares from 0 to 3 months (0.57 vs 1.91, p = 0.022), fewer flares 3-6 months (0 vs 1.05, p = 0.033), less severe flares as reported on VAS (3.64 vs 5.08, p = 0.018), and fewer recurrent gout flares (p = 0.001). Colchicine was well tolerated. CONCLUSION: Colchicine prophylaxis during initiation of allopurinol for chronic gouty arthritis reduces the frequency and severity of acute flares, and reduces the likelihood of recurrent flares. Treating patients with colchicine during initiation of allopurinol therapy for 6 months is supported by our data.

Arthritis, Gouty↗

PubMed1992

Kinetics of colchicine binding to purified beta-tubulin isotypes from bovine brain.

Tubulin, the constituent protein of microtubules, is an alpha beta heterodimer; both alpha and beta exist in several isotypic forms whose functional significance is not precisely known. The antimitotic alkaloid colchicine binds to mammalian brain tubulin in a biphasic manner under pseudo-first-order conditions in the presence of a large excess of colchicine (Garland, D. L. (1978) Biochemistry 17, 4266-4272). We have studied the kinetics of colchicine binding to purified beta-tubulin isotypes and find that each of the purified beta-tubulin isotypes binds colchicine in a monophasic manner. The apparent on-rate constants for the binding of colchicine to alpha beta II-, alpha beta III-, and alpha beta IV-tubulin dimers are respectively 132 +/- 5, 30 +/- 2, and 236 +/- 7 M-1 s-1. When the isotypes are mixed, the kinetics become biphasic. Scatchard analysis revealed that the isotypes differ significantly in their affinity constants (Ka) for binding colchicine. The affinity constants are 0.24 x 10(6), 0.12 x 10(6), and 3.31 x 10(6) M-1, respectively, for alpha beta II-, alpha beta III-, and alpha beta IV-tubulin dimers. Our results are in agreement with the hypothesis that the beta-subunit of tubulin plays a major role in the interaction of colchicine with tubulin. Our binding data raise the possibility that the tubulin isotypes might play important regulatory roles by interacting differently with other non-tubulin proteins in vivo, which in turn, may regulate microtubule-based functions in living cells.

Animals↗

PubMed2006

Colchicine therapy and the cognitive status of elderly patients with familial Mediterranean fever.

BACKGROUND: [corrected] Colchicine is widely used for treating gout and familial Mediterranean fever. However, studies in animal models have reported ill effects of colchicine on the central nervous system, including cognitive function. OBJECTIVES: To evaluate the cognitive status of elderly FMF patients on long-term colchicine treatment. METHODS: The study group consisted of 55 FMF patients aged 74 +/- 5, attending an FMF outpatient clinic and receiving colchicine treatment for 25.1 +/- 8.9 years. The Mini-Mental State Examination was used for cognitive evaluation. Patients' scores were compared with accepted age- and education-adjusted cutoff scores, population-based norms, and scores of a matched control group of 56 subjects. RESULTS: Individually, all colchicine-treated FMF patients scored well above the age- and education-corrected cutoff scores. Overall, there was a large difference, 5.0 +/- 1.6, from the expected cutoff points, in favor of the study group scores (P < 0.001). The individual scores of the control group were also above the cutoff points, however with a lower but still statistically significant difference (3.71 +/- 1.15 points, P < 0.001). Compared to population-based norms adjusted by age and education, the study group had significantly higher mean MMSE scores (27.2 +/- 2.2 vs. 25.5 +/- 2.4, P < 0.001). The control group's scores were also somewhat higher than expected, but not significantly so. CONCLUSIONS: Our results do not support the view that prolonged colchicine treatment may be associated with cognitive impairment. On the contrary, it is possible that long-term colchicine treatment may even confer protection against cognitive decline in patients with FMF.

Aged↗

PubMed1991

Long-term behavioral and neurochemical effects of intradentate administration of colchicine in rats.

Previous work in our laboratory has shown that the intradentate administration of colchicine produces time-dependent behavioral and neurochemical changes. Deficits in learning and memory and alterations in the signal transduction process for the cholinergic muscarinic receptor have been observed up to 12 weeks after colchicine treatment. To study the long-term effects of colchicine administration on cognitive function and the cholinergic system, 6 month-old male, Fischer-344 rats were injected with 2.5 micrograms of colchicine bilaterally in the dorsal and ventral hippocampus. Twelve months later the animals were tested for the acquisition of a spatial reference memory task in the Morris water maze for 8 days, with 4 trials of 60 seconds each day. At the completion of the behavioral testing, one set of rats from each treatment group was used for histochemical studies. The remaining animals were sacrificed, the hippocampi removed and used for the estimation of receptor-stimulated turnover of phosphoinositides (Pl). [3H]-inositol was incorporated into the hippocampal slices, and various receptor agonists (carbachol, norepinephrine, serotonin) used to stimulate Pl turnover in the presence of lithium. A significant deficit in acquisition in the water maze was observed in animals 1 year after colchicine administration. Neurochemical studies showed an increase in carbachol-induced Pl metabolism in the rat hippocampus 1 year post-lesion with colchicine. However, in contrast to results obtained 12 weeks after lesioning, no significant changes were observed in norepinephrine or serotonin-induced Pl metabolism 1 year after lesioning. Pirenzepine, a M1 receptor antagonist, produced a greater degree of inhibition (62%) in lesioned animals as compared to the age-matched controls (20%). Increased staining for acetylcholinesterase was found in the hippocampus of treated rats. This effect is similar to that observed 12 weeks after lesioning. These data suggest that the effects of colchicine on the cholinergic system are long-lasting and can be observed a year after treatment.

Acetylcholine↗

PubMed1985

Dendritic transport. I. Colchicine stimulates the transport of lysosomal enzymes from cell bodies to dendrites.

Injection of colchicine into the lateral cerebral ventricle of the rat was found to induce a paradoxical translocation of two lysosomal enzymes, dipeptidyl peptidase II (Dpp II) and acid phosphatase, from the soma of neurons to the dendrites. Following a single injection of colchicine, neuronal somata, which normally contain the bulk of these lysosomal enzymatic activities, become depleted of these enzymes, whereas dendrites become abnormally enriched. All neurons which contained these enzymes, except those of the mesencephalic nucleus of the trigeminal nerve, displayed this phenomenon. Lysosomal enzyme translocation into dendrites was observed in the mitral cell layer within 1 hr after a colchicine injection and could be induced in most neuronal populations by injections of colchicine as low as 25 micrograms. Five days after a 100-micrograms colchicine injection, a normal pattern of enzyme distribution was observed, indicating that the effect of colchicine was reversible. Enzyme translocation was not accompanied by gross changes in cell morphology, nor did it result in the specific loss of neuronal cell bodies which contained these enzymes. The results indicate that colchicine, under conditions known to inhibit axoplasmic transport, stimulates the transport of lysosomal enzymes from the cell body to the dendrites.

Acid Phosphatase↗

PubMedDate not supplied

Distribution of [3H]colchicine in brain and spinal cord areas following its intracerebroventricular or intra-spinal cord injection in rats.

Intracerebroventricular or intra-spinal cord (at lumbar level) injection of low doses of colchicine leads to irreversible urine retention. To learn whether colchicine induces this effect by diffusing from the sites of injection, we studied, using the above-mentioned routes of administration, the distribution of [3H]colchicine in brain and spinal cord areas as a function of time. The release of [3H]colchicine into the blood and its elimination via the renal route was studied as well. The results of these experiments show that after its intracerebroventricular injection, [3H]colchicine diffuses to brain areas that normally exert a facilitatory or inhibitory action on urine excretion but reaches the lumbar region in only modest amounts (0.02%). On the other hand, after its intra-spinal cord injection, [3H]colchicine remains at the site of injection, where the sacral micturition center is located. This suggests that intracerebroventricular or intra-spinal cord injected colchicine induces urine retention by exerting its action at two different levels of the neuronal pathway that regulates micturition, depending on the site of injection.

Animals↗

PubMed1988

Intradentate colchicine disrupts the acquisition and performance of a working memory task in the radial arm maze.

Rats were given bilateral injections of colchicine into the dorsal and ventral hippocampus to study the role of the dentate gyrus granule cells in the acquisition and performance of a spatial, working memory task in the radial arm maze. Three weeks after intradentate injections, rats were trained in a task in which all eight arms were baited prior to each daily trail. For up to 20 days of training, colchicine-treated rats were significantly impaired in the performance of the task. In another study, rats received 20 days of training and then were given intradentate colchicine. Three weeks later, the performance of the colchicine-treated rats was impaired for up to 20 days of testing. A third experiment tested the ability of colchicine-treated rats to learn a task in which the same four arms of the maze were baited, while the remaining arms were never baited. Colchicine-treated rats were significantly impaired in their ability to perform this version of the task. Histological verification indicated that colchicine resulted in a relatively select loss of granule cells, while sparing pyramidal cells in the hippocampus. These data suggest that the hippocampus plays an integral role in the performance of the place tasks used in these experiments.

Animals↗

PubMed1987

[Colchicine in dermatology].

Colchicine is one of the oldest drugs known to us. During the last few years, it has been increasingly applied in the treatment of systemic dermatoses. Particularly in dermatoses mediated by neutrophils, colchicine has settled among other therapies. With regard to Behçet's disease, it has even become the treatment of choice. The present review deals with further dermatological disorders sensitive to colchicine; in addition, we mention those dermatoses which do not show any therapeutic response to colchicine. The treatment with colchicine requires profound knowledge of the pharmacokinetics and mode of action regarding this substance, as well as the possible side effects. This knowledge allows safe and responsible treatment with colchicine. It has to be considered, however, that in the Federal Republic of Germany colchicine has not been registered for dermatological indications yet.

Behcet Syndrome↗

PubMed1985

The effects of colchicine analogues on the reaction of tubulin with iodo[14C]acetamide and N,N'-ethylenebis(iodoacetamide).

We have previously found (Ludueña, R. F., and Roach, M. C. (1981b) Biochemistry 20, 4444-4450) that colchicine and podophyllotoxin inhibit the alkylation of tubulin by iodo[14C]acetamide and the formation of an intrachain cross-link in the beta-tubulin subunit by N,N'-ethylenebis(iodoacetamide) (EBI). It was not clear whether these effects were due to conformational changes in tubulin induced by drugs or to direct steric blockage of the sulfhydryl groups involved. In an effort to characterize further these phenomena, we have examined the effects of single-ring and bicyclic analogues of colchicine on the reaction of tubulin with iodo[14C]acetamide and EBI. We have found that neither the A-ring analogues, 3,4,5-trimethoxybenzyl alcohol, 3,4,5-trimethoxybenzaldehyde, 2,3,4-trimethoxybenzaldehyde, and benzaldehyde, nor the C-ring analogues, tropolone and tropolone methyl ether, inhibited alkylation. In contrast, colchicine, podophyllotoxin, and nocodazole and the bicyclic analogues, 5-(2',3',4'-trimethoxyphenyl)-2-methoxytropone and combretastatin, inhibited tubulin alkylation. Since the presence of a bond joining the A and C rings seems to be the determining factor in the suppression of alkylation, it is likely that inhibition by colchicine of the reaction with iodo[14C] acetamide is due largely to a conformational change induced by colchicine. A different pattern was obtained when the effects on cross-link formation by EBI were examined. Here, all the A-ring analogues, the bicyclic analogues, and colchicine, podophyllotoxin, and nocodazole all inhibited formation of the cross-link, whereas the C-ring analogue tropolone methyl ether did not inhibit cross-link formation. Since compounds whose effect on alkylation is markedly different have the same effect on cross-link formation, it is possible that this effect is a steric one and that perhaps the A-ring of colchicine binds to tubulin very close to one of the sulfhydryls involved in the intrachain cross-link formed by EBI in beta-tubulin.

Alkylation↗

PubMed1979

[Genetic study of the resistance of mouse somatic cells to colchicine (high resistance level)].

The studies of the high level of colchicine resistance of mouse L cells have shown that two mutagens (EMS and NMM) do not induce cell variants resistant to 8 microgram/ml of colchicine in the population of mouse heteroploid L-53 cells (subline of L cells, the level of colchicine resistance 140) and that colchicine resistance of L-53 cells gradually diminishes when cells are propagated in non-selective conditions: after 1 month it diminishes 2-fold, after 3 month--9-fold. The extent of the decrease of the drug resistance was the same in 6 independent cultures obtained from the inoculum of 200 cells and in control cultures propagated by large quantities of cells. These data coincide with the results of the previous studies of lower level of colchicine resistance. In both studies the frequency of the occurrence of colchicine resistant variants in selective medium was about 2.10(-4). These data are consistent with the hypothesis that colchicine resistance of mouse L cells is not due to a gene mutation.

Animals↗

PubMed1978

Ultrastructural study of the persistence of colchicine-induced cytological changes in Harding-Passey melanoma.

Electron microscopic observations were undertaken on Harding-Passey melanoma in control tumors, colchicine-treated tumors, and tumors that were passed through five transplantations in mice subsequent to colchicine treatment. The untreated Harding-Passey melanoma tumor was composed of pleomorphic cells the cytoplasm of which contained tubulovesicular mitochondria and numerous free and membrane-attached ribosomes. Type A virus particles were observed in both mitotic and interphase cells. Colchicine-treated tumors exhibited several typical colchicine mitotic cells arrested in metaphase. A most significant feature of the colchicine administration was the appearance of microfilaments in both interphase and mitotic cells, a feature not observed in cells of the untreated tumor. Electron microscopy of colchicine-treated tumors carried through five transplantations at biweekly intervals revealed the presence of microfilaments in tissues fixed at each of the transplantations. It therefore appears that the cytological effects of colchicine resulting in the appearance of filaments in melanocytes of the Harding-Passey melanoma are more enduring than they were initially presumed to be.

Animals↗

PubMed1983

Effect of colchicine on immunoregulatory abnormalities in familial Mediterranean fever.

The effect of colchicine on immunoregulatory T lymphocytes in children with familial Mediterranean fever (FMF) was studied. Concanavalin A (Con A)-induced suppressor cell function was significantly (P less than 0.0001) decreased in five untreated FMF patients (15 +/- 3%, mean +/- s.e.) as compared to six age matched paediatric controls (46 +/- 3%) and eight healthy adults (49 +/- 4%). When the five untreated FMF patients' mononuclear cells were pre-incubated in vitro with Con A plus 10(-5) M colchicine, their suppressor cell function was significantly increased (52 +/- 10%, P less than 0.01). Similarly, oral colchicine treatment (0.5 mg twice daily) significantly (P = 0.02) increased the five FMF patients' Con A-induced suppressor cell function to levels (34 +/- 6%) that were not significantly (P greater than 0.05) different than the paediatric controls or the healthy adults. The percentage of OKT8+ cells (but not OKT3+ or OKT4+ cells) was significantly (P less than 0.0001) decreased in 10 untreated FMF patients (16.0 +/- 0.9) as compared to 10 paediatric controls (27.6 +/- 2) or 10 healthy adults (25.7 +/- 0.6). The 10 untreated FMF patients had a significant (P less than 0.002) increase in the OKT4/OKT8 ratio (2.41 +/- 0.13) as compared to 10 FMF patients treated with 0.5 mg twice daily of colchicine (1.81 +/- 0.08), 10 pediatric controls (1.47 +/- 0.2), or 10 healthy adults (1.78 +/- 0.11). Colchicine appears to have corrected the FMF patients' elevated OKT4/OKT8 ratio by both decreasing the percentage of OKT4+ cells and increasing (but only partially correcting) the percentage of OKT8+ cells. Thus FMF patients have a suppressor cell deficiency in which colchicine treatment corrects their deficiency of Con A-induced suppressor cell function and their elevated OKT4/OKT8 ratio. This raises the possibility that colchicine might be potentially useful as an immunomodulating drug in treating patients with autoimmune or allergic diseases associated with a suppressor cell deficiency.

Adolescent↗

PubMed1983

Effects of colchicine on the intestinal transport of endogenous lipid. Ultrastructural, biochemical, and radiochemical studies in fasting rats.

The involvement of microtubules in the transepithelial transport of exogenous lipid in intestinal absorptive cells has been suggested. Using electronmicroscopic, biochemical, and radiochemical methods, we have studied the effects of the antimicrotubular agent colchicine on the intestinal mucosa and on the intestinal transport of endogenous lipid of rats in the fasting state. After colchicine treatment, the concentration of triglycerides in intestinal mucosa of rats fasted for 24 h doubled, and electron microscopic studies showed a striking accumulation of lipid particles in absorptive epithelial cells of the tips of jejunal villi. These findings suggest that colchicine interferes with the intestinal transepithelial transport of endogenous lipoproteins. Additional studies, using an intraduodenal pulse injection of [14C]linoleic acid, showed that colchicine does not affect the uptake of fatty acids by intestinal mucosa. However, it had divergent effects on fatty acid esterification, enhancing their incorporation into triglycerides relative to phospholipids, and caused a significant accumulation of endogenous diglycerides, triglycerides, and cholesterol esters within the absorptive intestinal epithelium. Detailed ultrastructural and morphometric studies revealed a decrease of visible microtubules, and a displacement of the smooth and rough endoplasmic reticulum and Golgi apparatus. Furthermore, it is shown that after colchicine treatment, microvilli appear at the lateral plasma membrane of intestinal absorptive cells, a change not previously reported to our knowledge. Thus, our study shows that (a) colchicine causes significant changes in enterocyte ultrastructure and (b) colchicine perturbs the reesterification of absorbed endogenous fatty acids and their secretion in the form of triglyceride-rich lipoproteins from the enterocyte.

Animals↗

PubMed1980

Colchicine binding to antibodies.

Antibodies to colchicine have been prepared by injecting rabbits with an antigen prepared by coupling deacetylcolchicine to bovine serum albumin with a water-soluble carbodiimide. Sera of high titer were obtained with apparent dissociation constants for colchicine ranging from 5 to 17 nM. Binding was rapid and occurred at low temperatures. The chemical specificity of the binding site(s) resembled that in tubulin for the A and B rings of colchicine. Unlike tubulin, the antibody binding site tolerated numerous changes in the tropolone moiety (C ring). In contrast to tubulin, binding of colchicine to the antibody site did not promote fluorescence. The colchicine binding capacity of the antibody was high enough to prevent colchicine fluorescence in the presence of tubulin and to restore polymerization in colchicine-inhibited tubulin preparations.

Animals↗

PubMed1995

Colchicine-induced lactose malabsorption in patients with familial Mediterranean fever.

Abdominal pain and diarrhea are frequent side effects of chronic colchicine therapy. Drug-induced lactose deficiency has been demonstrated in the experimental animal. Lactose malabsorption was assessed by the lactose breath test in 23 patients with familial Mediterranean fever (FMF) receiving colchicine for 0.25-15 years (mean 3.16). Twenty FMF patients not receiving colchicine and 38 non-FMF lactose malabsorbers served as controls. Patients receiving colchicine had a significantly higher percentage of lactose malabsorption (20/23, 87%) versus nontreated FMF patients (13/20, 65%; P < 0.05). Lactose intolerance was also more prevalent in colchicine-treated patients (17/23, 74%) versus nontreated FMF (5/20, 25%; P < 0.0005) and control lactose malabsorbers (16/38, 42%; P < 0.01). Of the 12 patients investigated before and 3 months after colchicine administration, 7 showed induction or aggravation of lactose malabsorption. The lactose-free diet resulted in partial improvement of symptoms. Colchicine induces significant lactose malabsorption in FMF patients and this is partially responsible for the gastrointestinal side effects of the drug.

Abdominal Pain↗

PubMed1994

Compensatory changes in the hippocampus following intradentate infusion of colchicine.

Direct infusion of colchicine into the dentate gyrus of the hippocampus kills granule cells and elicits behavioral, neurochemical and neuroanatomical changes. Colchicine-treated rats are less sensitive to the behavioral effects of cholinergic muscarinic receptor antagonists and more sensitive to cholinergic agonists. These behavioral changes are associated with time- and dose-dependent alterations in the cholinergic signal transduction mechanism. Carbachol-stimulated turnover of phosphoinositides is increased in the hippocampus of colchicine-treated rats; similar changes are not observed in the cortex or striatum of colchicine-treated animals. Intradentate colchicine produces a significant increase in choline- acetyltransferase activity and staining for acetylcholinesterase activity in the hippocampus, suggesting reactive synaptogenesis of cholinergic fibers. Other studies have shown that the integrity of the septohippocampal pathway is necessary for these colchicine-induced compensatory changes to occur. It is suggested that the mechanism for these neurochemical changes in colchicine-treated animals may be occurring via alterations in negative feedback control of receptor-G-protein-mediated phosphoinositide hydrolysis.

Animals↗

PubMed1977

[Use of colchicine in studying the proliferative activity of chicken embryos].

Manifestation of mitotic activity of colchicin in 4- and 5-day-old chick embryos was studied under different modes of colchicin injection into the eggs. Three methods were tested: colchicin solution was injected into the serous-amniotic cavity (1) and into the yolk sac (2) and also by dripping on the serous membrane over the enbryo (3). Perfect metastatic effect was observed only when colchicin was used in concentration of 1 X 10(-4) g/ml and injected by the third mehtod. Increase in the solution volume over 0.1 ml resulted in a greater percentage of embryo death. Lack of a definite inhibitory action after colchicin injection into the serous-amniotic cavity might be explained by decrease of the substance concentration as a result of its dilution by the cavity fluid. A complete lack of blocked mitoses in the embryo tissues after colchicin injection into the yolk sac can be explained, according to the authors, by the presence, in the yolk, of a great number of ovoflavins capable to inhibit mitotic activity of colchicin.

Animals↗

PubMed1997

Colchicine activates actin polymerization by microtubule depolymerization.

Swiss 3T3 fibroblasts were treated with the microtubule-disrupting agent colchicine to study any interaction between microtubule dynamics and actin polymerization. Colchicine increased the amount of filamentous actin (F-actin), in a dose- and time-dependent manner with a significant increase at 1 h by about 130% over control level. Confocal microscopic observation showed that colchicine increased F-actin contents by stress fiber formation without inducing membrane ruffling. Colchicine did not activate phospholipase C and phospholipase D, whereas lysophosphatidic acid did, indicating that colchicine may have a different mechanism of actin polymerization regulation from LPA. A variety of microtubule-disrupting agents stimulated actin polymerization in Swiss 3T3 and Rat-2 fibroblasts as did colchicine, but the microtubule-stabilizing agent taxol inhibited actin polymerization induced by the above microtubule-disrupting agents. In addition, colchicine-induced actin polymerization was blocked by two protein phosphatase inhibitors, okadaic acid and calyculin A. These results suggest that microtubule depolymerization activates stress fiber formation by serine/threonine dephosphorylation in fibroblasts.

3T3 Cells↗