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Further dopaminergic supersensitivity to dopamine agonists by subchronic administration of haloperidol in rats treated with colchicine.

Effects of subchronic administration of haloperidol on the circling behavior induced by dopamine agonists were examined in rats treated with colchicine. Methamphetamine and apomorphine produced contralateral or ipsilateral rotation in colchicine-treated rats, and these circling behaviors were significantly increased by subchronic treatment with haloperidol. These results suggest that development of supersensitivity following colchicine and subchronic haloperidol may occur through different mechanisms.

Animals↗

Effect of colchicine on the depletion and replenishment of cytoplasmic glucocorticoid receptor in rat liver after administration of glucocorticoid.

Pretreatment of rats with colchicine (3 mg/kg body weight) modified the time course of depletion of the cytoplasmic binding sites for 3H-dexamethasone after administration of prednisolone (0.5 or 1.5 mg/kg body weight). Colchicine also decreased the rate of the cytoplasmic receptor replenishment which was confirmed by application of this drug after completion of the cytoplasmic receptor translocation to nuclei (30 min after prednisolone injection). Addition of colchicine to the incubation mixture for in vitro binding of 3H-dexamethasone-labelled liver cytosol to isolated liver nuclei suspended in TKMS buffer (50 mM Tris-HCl, pH 7.5, 50 mM KCl, 5 mM MgCl2 and 250 mM sucrose) evoked no measurable changes in the rate of the nuclear binding.

Animals↗

Metabolic transformation of colchicine, III. Inhibition of phosphatases by the metabolite O10-demethylcolchicine (colchiceine) and their reactivation by divalent cations.

Colchicine and some of its metabolites and derivatives were investigated regarding their inhibitory action against alkaline phosphatases from E. coli and calf intestine, and against acid phosphatase from potato. Colchicine itself was essentially ineffective, also its metabolites O2-demethyl- and O3-demethylcolchicine. The metabolite O10-demethylcolchicine (= colchiceine) was found to be a powerful, non-competitive inhibitor for all three phosphatases with Ki in the range of 0.45-6.0mM. Amongst the derivatives of colchicine, colchiceyltaurine proved to be a non-competitive inhibitor of acid phosphatase (Ki=3.0mM); desacetylcolchiceine behaved like colchiceine. The inhbitory actions of colchiceine and desacetylcholchiceine could be completely reversed by the addition of Mg2, Ca2, or Zn2, respectively. This interaction with divalent cations demonstrates a novel type of action of the metabolite colchiceine when compared with its mother alkaloid and is possibly of major biological significance.

Acid Phosphatase↗

Secretion of lamellar bodies in type II pneumocytes in organoid culture: effects of colchicine and cytochalasin B.

Lamellar bodies are the morphological correlate to the alveolar surface-active agent. Diminished synthesis of this surfactant in newborns results in the respiratory distress syndrome. Secretion of lamellar bodies and its dependence on the cytoskeleton are not yet well understood and are still controversially discussed in the literature. We therefore used an organoid culture system of fetal mouse lung cells to investigate electron microscopically secretion of lamellar bodies and influence of both colchicine and cytochalasin B on the secretion process. Secretion of lamellar bodies is to be considered as an eccrine secretion, because no other cytoplasmic components were extruded. It includes a very fast component in opening of the secretory vacuole. Synthesis, but not secretion, was inhibited by colchicine; secretion, but not synthesis, was inhibited by cytochalasin B. Furthermore, formation of the histotypic structures in vitro and deposition of the basal lamina were disturbed by cytochalasin B, but not altered by colchicine. After short-term treatment, these effects turned out to be reversible. The results indicate that synthesis of lamellar bodies depends on an intact microtubular system, whereas secretion requires actin filaments in a functional state.

Animals↗

Taxol, cytochalasin B and colchicine effects on fibroblast migration and contraction: a role in glaucoma filtration surgery?

Migration and contraction are fibroblast activities in scar tissue formation which may contribute towards the failure of trabeculectomies. We attempted to modify the migration and contraction of Tenon's capsule fibroblasts in vitro using the drugs taxol, cytochalasin B and colchicine. Migration assays were conducted in 48-well micro-chemotaxis chambers, using rabbit aqueous humour which has been previously identified as a powerful chemoattractant for Tenon's fibroblasts, and fibronectin as the stimuli for migration. All three drugs inhibited the migration of fibroblasts to both fibronectin and aqueous humour, with maximal activity seen at 10(-6)M (taxol), 10(-5)M (cytochalasin B), and 10(-3) M (colchicine). In a single cell contractile assay in which contraction of whole fibroblasts was initiated with exogenous adenosine triphosphate (ATP), taxol and colchicine showed anticontractile activity, maximal at 10(-5)M and 10(-3)M respectively, but cytochalasin B was ineffective. The significance of the activities of these drugs in relation to their proposed use for improving the success of trabeculectomies is discussed.

Actins↗

Colchicine toxicity--clinical features and treatment. Massive overdose case report.

This is a report of colchicine poisoning in a 24-year-old woman. She developed multiple organ failure and bone marrow suppression after the suicidal ingestion of 50 (1 mg) colchicine tablets. The pancytopenia responded to granulocyte colony-stimulating factor 300 micrograms on days 4, 5, 6, and 8. Although anticolchicine monoclonal antibody administration is the only specific therapy described, intensive supportive care including granulocyte colony-stimulating factor administration can facilitate recovery from severe colchicine intoxication.

Adult↗

Milk yield and secretion composition following intramammary infusion of colchicine.

Twenty-five lactating dairy cows were in a split block design to investigate effects of intramammary colchicine infusion on milk yield and composition. Right udder halves of 15 cows were infused with colchicine while left udder halves received no infusion. Ten cows received no infusion in either right or left udder halves. At 24 h postintramammary colchicine infusion, milk yield decreased 38.5% in treated halves and 9.3% in control halves. Udder halves of uninfused cows had an 8.7% reduction. Milk from treated halves compared to untreated halves had elevated somatic cells, serum albumin, and pH. Citrate and the molar ratio of citrate to lactoferrin were lower. Lactoferrin and immunoglobulin G did not differ between infused and uninfused halves; however, they increased in treated halves postinfusion as compared to preinfusion. Serum albumin and citrate increased, and the index of selective accumulation of immunoglobulin G decreased in left halves. Control cows did not differ.

Animals↗

Synchronization of Plasmodium falciparum in continuous in vitro culture: use of colchicine.

Cultures of Plasmodium falciparum with parasitemias of 3-5% were exposed to 4 mM colchicine for 24 hours. Synchrony was observed 48 hours after treatment, and the cultures remained synchronous for more than two replicative cycles. The percentage of ring stage parasites reached peaks of over 90% at 72 and 120 hours. The percentage of schizonts reached a peak of 70% at 144 hours. Parasitemias in both colchicine-treated and untreated control cultures reached peaks of over 20% 120 hours after colchicine treatment.

Animals↗

Colchicine effect in a colonic hyperplastic polyp. A lesion mimicking serrated adenoma.

Colchicine effect has been described recently in gastrointestinal biopsies, where it can result in accumulation of metaphase mitoses and epithelial disorganization. We describe the case of a colonic hyperplastic polyp with colchicine effect from a 52-year-old woman who was receiving colchicine for primary biliary cirrhosis. Biopsy of the polyp revealed prominent metaphase mitoses and focal loss of nuclear polarity in the surface epithelium, features that mimicked a serrated adenoma. Distinguishing between hyperplastic polyp and serrated adenoma is important because of the different management implications and the increased potential for neoplastic progression in the latter.

Adenoma↗

Dangers of low-dose colchicine in patients with renal failure.

(1) Life-threatening colchicine intoxication can occur in patients with renal failure, even with low-dose regimens. (2) Diarrhoea, nausea and vomiting are the first manifestations of overdose. Colchicine must be withdrawn immediately to avoid severe complications (especially haematological and neuromuscular). (3) Colchicine must not be prescribed without first assessing creatinine clearance (using the Cockroft formula, for example), especially in elderly patients.

Colchicine↗

Effect of colchicine and its derivatives on the expression of selected isoforms of cytochrome P450 in primary cultures of human hepatocytes.

The study addressed the effect of colchicine and its derivatives on the protein levels of cytochrome P450 (CYP) 1A2, 2A6, 3A4, 2C9/19, and 2E1 isoforms. Primary human hepatocyte culture was the model of choice. Levels of individual CYP isoforms were detected using immunoblotting. Colchicine caused an increase of CYP2E1 protein content, colchiceine and N-deacetylcolchiceine induced isoforms CYP2C9, 2E1 and 3A4 whereas colchicoside induced CYP2C9 and 2E1. The levels of CYP1A2 and 2A6 were unaffected by any of tested compounds. Demecolcine and 3-demethylcolchicine had no effect on any studied P450 isoform. Since colchicine is an exclusive substrate of CYP3A4 whereas it induces CYP2E1, there is a suspicion rather at protein stabilization than at gene induction concerning induction origin.

Cells, Cultured↗

Binding of colchicine to purified microtubule protein.

The binding of colchicine to tubulin, purified by two cycles of assembly-disassembly, has been studied. Equilibrium studies indicated a dissociation constant which declined during incubation approaching a minimum value of approximately 0.30 times 10- minus 6 M after 13 hours of incubation. Because tubulin is unstable during prolonged incubation (t1/2 of 5.2 hours for free tubulin, t1/2 of 12.5 hours for tubulin bound to colchicine), the equilibrium Kd was felt to be an overestimation of the true Kd. The rate constant of dissociation (k-1 equal to 0.009 hour- minus 1 hour- minus 1) and the rate constant of association (k1 equal to 0.37 times 10-6 M-minus 1) were measured under conditions designed to circumvent or correct for tubulin instability. The dissociation constant determined by the ratio k-1/k1 was 0.024 times -minus 6 M. To determine whether the discrepancy between the "equilibrium" and "kinetic" determined dissociation constants could be accounted for on the basis of tubulin instability, the binding reaction was computer-simulated using the measured association and dissociation rate constants and the rate constants for decay of bound and free tubulin. Computer simulation was in close agreement with the experimentally determined behavior of the reaction during a 13-hour incubation. It is concluded that the Kd determined by equilibrium methodology results in a considerable overestimation due to the instability of tubulin, and that the best estimate for the Kd of the colchicine-tubulin equilibrium is the value determined by the ratio of the rate constants.

Animals↗

Successful treatment of familial Mediterranean fever attacks with thalidomide in a colchicine resistant patient.

Colchicine is the treatment of choice in familial Mediterranean fever (FMF) both for attacks and for prevention of secondary amyloidosis. The overall non-responder rate varies from 5-10 to 40%. Thalidomide is known to blunt the acute phase response. We report the efficacy of the addition of thalidomide to colchicine in controlling the febrile attacks and acute phase response in a patient with FMF resistant to 2 mg colchicine per day.

Colchicine↗

[A case of Behçet's disease associated with neuromyopathy induced by combination therapy with colchicine and cyclosporin].

A 61-year-old man with incomplete Behçet's disease was admitted to our hospital because of weakness and muscle pain in August 2001. The patient was diagnosed as having incomplete Behçet's disease because of oral aphtha, genital ulcer and uveitis. He had been administered with colchicine since December 1999. Cyclosporin was added in June 2000, because of repeated ocular attacks. In May 2001, he noticed weakness of proximal limb muscles. In three months, severe generalized muscle pain and numbness in his hands progressed. Laboratory findings showed elevation of muscular enzyme, serum creatinine, and hepatic transaminases. Electromyography and nerve conduction studies indicated myopathy and mild polyneuropathy, respectively. On diagnosis as drug induced neuromyopathy, colchicine administration was stopped. But, severe muscle pain continued. Thus, the cyclosporin dose was also reduced. Seven days later, weakness and muscle pain disappeared and laboratory findings markedly improved. These data indicate that the pathogenesis of neuromyopathy in this case was closely related to colchicine and cyclosporin. Caution will be needed in using these drugs for patients with Behçet's disease.

Behcet Syndrome↗

Differential effects of colchicine on central dopaminergic neuronal activity and prolactin secretion in estrogen-primed ovariectomized rats.

Colchicine is a potent chemical that disrupts the assembly of microtubulin and affects the integrity of cytoskeleton. It is commonly used to block the axonal transport in neurons. Central administration of colchicine (48 microg/3 microl/rat) two days earlier significantly lowered 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum and nucleus accumbens, both in the morning and in the afternoon. Median eminence DOPAC levels exhibit a diurnal change between morning and afternoon as previously shown. Colchicine treatment lowered and elevated median eminence DOPAC levels in the morning and afternoon, respectively. The estrogen-induced prolactin surge was also blocked. The findings indicate that neuronal inputs are necessary for maintaining basal activities in all dopaminergic neurons, while an inhibitory one predominates in the afternoon for TIDA neurons.

3,4-Dihydroxyphenylacetic Acid↗

The activity of antioxidant enzymes in Arabidopsis thaliana exposed to colchicine and H2O2.

Studies on the possible interference of colchicine and H2O2 with the activity of some antioxidant enzymes were carried out on Arabidopsis thaliana v. Columbia grown in Murashige and Skooge nutrient medium. Measurements of superoxide dismutase (SOD), guaiacol peroxidase (POX), ascorbate peroxidase (APX) and catalase (CAT) activities were conducted spectrophotometrically. In the presence of colchicine, SOD activity increased, while CAT, APX and POX activities decreased. Inhibitory H2O2 effects on the activity of the enzymes were found. Colchicine pre-treatment resulted in an increase in CAT activity and a further increase in SOD activity in plants treated with H2O2.

Antioxidants↗

The protective effect of colchicine on bleomycin-induced pulmonary fibrosis in rats.

With the purpose of evaluating the therapeutic effect of colchicine on lung fibrosis in rats, bleomycin A5 (BLM-A5) was injected intratracheally to produce a lung fibrosis model. The animals were then treated with colchicine, 50 micrograms/d i.m. One month later, collagen fiber deposition scores (stained by Masson trichrome) were significantly lower in the treated group than in the untreated group (P less than 0.01). This result was proved further by assaying total lung hydroxyproline content (P less than 0.05). Histopathologic findings showed that the proliferation of fibroblasts dropped slightly in the treated group as compared with the untreated group. From this study, we conclude that colchicine has certain antifibrotic effects and may be used in the treatment of pulmonary fibrosis.

Animals↗