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PubMedDate not supplied

Effects of colchicine on the synthesis and transport of albumin: a combined electron cytochemical and autoradiographic study.

We investigated the intracellular transport of albumin in the livers of rats treated with colchicine using immunoperoxidase study as well as combined immunoelectron microscopy and autoradiography with [3H]-leucine. Immunoreaction of albumin was observed in all hepatocytes. Its subcellular location was in the rough endoplasmic reticulum, Golgi apparatus and lysosomes. After the injection of [3H]-leucine through the portal vein, a combined technique revealed accumulated grains on the albumin-positive Golgi apparatus or the albumin-positive vesicles in the vicinity of the Golgi apparatus. These findings suggest that albumin transport from the Golgi apparatus to sinusoids is disturbed by colchicine. Enzyme histochemistry showed many acid phosphatase-positive lysosomes in hepatocytes of the liver treated with colchicine. Albumin retained in the vicinity of the Golgi apparatus may be digested by lysosomes. An in situ hybridization study with isotopes revealed the presence of silver grains for albumin mRNA in all hepatocytes of livers treated or untreated with colchicine; there was no significant difference in the number of silver grains in the two groups. Therefore, colchicine has very little effect on albumin synthesis in the liver.

Albumins↗
PubMed1987

Does colchicine work? The results of the first controlled study in acute gout.

We have performed the first controlled study of colchicine in acute gout, to determine its efficacy and toxicity, and to define the natural history of acute gout. Two-thirds of colchicine-treated patients improved after 48 hours, but only one-third of the patients receiving placebo demonstrated similar improvement. The colchicine-treated patients responded earlier; significant differences from placebo were shown after 18-30 hours. All patients given colchicine developed diarrhea after a median time of 24 hours (mean dose of colchicine 6.7 mg). This side effect occurred before relief of pain in most patients.

Acute Disease↗
PubMed1991

Plasma protein catabolism in ethanol- and colchicine-treated liver slices.

The present study was conducted to determine whether the antisecretory agents colchicine and ethanol affect the intracellular degradation of plasma proteins in rat liver. Plasma proteins were prelabeled in vivo with [3H]leucine and their levels were monitored immunochemically in both the medium and extracts of rat liver slices incubated alone or in the presence of 50 microM colchicine or 25 mM ethanol. Compared with those left untreated, colchicine-treated slices had a 40-55% lower secretory capacity and, at one point, showed significant hepatocellular retention of total plasma proteins. Plasma protein secretion by ethanol-treated liver slices was 22-32% lower than controls, but there was no detectable retention of unsecreted plasma proteins in the ethanol-treated liver tissue. In all experiments, the total radioactivity in plasma proteins (i.e., the immunoprecipitable radioactivity in the liver plus that in the medium) decreased with time in a manner suggestive of intracellular degradation. Regression analyses of the rates of degradation of presecretory proteins revealed that compared with controls, plasma protein catabolism was accelerated 57% in colchicine-treated slices. In ethanol-treated liver slices, there was a 50% increase in the degradation of total plasma proteins and a 46% increase in albumin catabolism. In all cases, degradation was intracellular. These findings indicate that inhibition of hepatic protein secretion by either colchicine or ethanol is associated with accelerated catabolism of unsecreted plasma proteins, suggesting that hepatocellular degradative processes are responsive to changes in the levels of presecretory proteins and/or perturbations of the secretory process.

Animals↗
PubMed1976

A colchicine-sensitivity test for leukaemic lymphocytes.

Non-dividing lymphocytes from patients with chronic lymphocytic leukaemia were more sensitive than normal lymphocytes to reagents as prednisolone, cytarabine, vincristine and colchicine. The maximum difference was obtained when the cells were incubated with colchicine at 37 degrees C for 20 h. The sensitivity was measured by a 'sensitivity index' which was an estimate of the average percentage of lymphocytes killed by 1.0 and 0.1 mug/ml of colchicine. The index was 0-15% for lymphocytes from the blood of 14 normal persons and was 61-98% for 23 of 25 leukaemic patients with absolute lymphocyte counts of 8,000 X 10(9)/l or more. 3 of 4 untreated patients with presumptive diagnoses of early leukaemia had low absolute counts of 3,300 to 7,600 X 10(9) lymphocytes/l and high sensitivity indices of 41 to 83%. Tests on treated patients with lymphocytes counts less than 8,000 X 10(9)/l suggested a correlation of the index with remission and relapse. Hairy cells from 3 patients with hairy cell leukaemia were resistant to colchicine. Sensitivity to colchicine seemed useful at a test for leukaemic lymphocytes and as an aid in the haematologic evaluation of patients with chronic lymphocytic leukaemia and malignant lymphoma.

B-Lymphocytes↗
PubMed1979

Inhibition of fast axonal transport and microtubule polymerization in vitro by colchicine and colchiceine.

The effects of colchicine and colchiceine on fast axonal transport in frog sciatic nerves were studied in vitro. Colchiceine inhibited the transport to about the same extent as colchicine. Preincubation at low temperature potentiated the inhibitory effect of either drug. The polymerization of purified brain tubulin was inhibited by colchiceine at 5-10 times higher concentrations than colchicine. The similarity of the effects obtained with colchicine and colchiceine indicates that both drugs arrest axonal transport by interfering with microtubule function. Colchicine and colchiceine did not affect the levels of high energy phosphates (ATP and CrP) in frog nerves indicating that a reduced energy supply was not responsible for the arrested transport.

Adenosine Triphosphate↗
PubMed1990

Colchicine inhibits the effects of secretin on pancreatic duct cell tubulovesicles and HCO3- secretion in the pig.

Secretin stimulation clears the cytoplasm of intralobular pancreatic duct cells in pigs of tubulovesicles and causes these cells to secrete HCO3- into the pancreatic juice. To determine whether the clearance of cytoplasmic tubulovesicles involves the microtubule system and is important for initiation of HCO3- secretion, the effect of the microtubule poison colchicine on duct cell morphology and pancreatic HCO3- secretion was measured in anaesthetized pigs. Before colchicine, secretin reduced the density of tubulovesicles in the cytoplasm of pancreatic duct cells from 92 +/- 8 U to 8 +/- 2 U and initiated pancreatic secretion of 176 +/- 21 mumols min-1 HCO3-. After colchicine, secretin failed to lower duct cell tubulovesicle density and caused the secretion of only 77 +/- 14 mumols min-1 HCO3-. By contrast, lumicolchicine, an isomer of colchicine that does not affect microtubules, did not inhibit pancreatic HCO3- secretion. Colchicine did not reduce carbonic anhydrase or Na,K-ATPase activities in in-vitro assays. The clearance of tubulovesicles from the cytoplasm of pancreatic duct cells therefore seems to be microtubule-dependent and important for the pancreatic HCO3- secretion.

Animals↗
PubMed1994

Changes in slow axonal transport of tubulin induced by local application of colchicine to rabbit vagus nerve.

The biochemical and morphological responses of the rabbit vagus nerve to local application of colchicine and to nerve crush were investigated. Fourteen days after the cervical vagus nerve had been crushed or subjected to local application of colchicine for 2 h, nodose ganglia of anaesthetized rabbits were either injected with [35S]methionine or [3H]leucine for studies of slow and fast axonal transport, respectively, or prepared for light microscopical examination. The radio-labelled proteins of the faster of the two slow transport groups (SCb; 25-30 mm day-1) were separated by one- or two-dimensional polyacrylamide gel electrophoresis and both radio-labelled tubulin and actin were quantified by densitometry from resulting fluorographs of gels. A relative increase in radio-labelled tubulin was found in SCb in the crushed and colchicine-treated nerves; this increase persisted for up to 50 days after nerve crush. Morphological changes in nerve cell bodies induced by colchicine were similar, but smaller in magnitude than those in crushed nerves. It is concluded that a temporary arrest of axonal transport produced by colchicine can lead to a redistribution of tubulin transport comparable with that found in regenerating nerve.

Animals↗
PubMed1975

Action of colchicine on axonal flow and pituicytes in the hypothalamopituitary system of the rat.

Changes in the hypothalamo-pituitary tract and the pituicytes of the rat were studied after intrathecal and intraperitoneal injections of colchicine. Radioautography with 35S-cysteine demonstrates that intrathecal colchicine prevents the migration of neurosecretory granules from the supraoptic and paraventricular nuclei to the posterior lobe of the pituitary. This results in accumulations of neurosecretory granules and in the formation in the axons of elongated structures resembling neurosecretory products, although they sometimes have a fibrillary content. Neurotubules appear to remain intact in these conditions. The stimulation of the posterior pituitary by dehydration, in particular after injection of the diuretic furosemide, leads to an increased activity of pituicytes. When colchicine is injected at the same time as furosemide, a considerable new formation of centrioles is observed in the pituicytes. These become associated with ciliary vesicles, and form numerous cilia of the 9 + 0 type. An increased number of centrioles is also seen in the endothelial cells of the posterior lobe of the pituitary. These apparently paradoxical results were briefly discussed in relation to the action of colchicine on neurotubules and axonal flow and to the limited data from the literature indicating a stimulation of cilia formation under the action of colchicine and other drugs.

Animals↗
PubMed1998

Cell death, phagocytosis, and neurogenesis in mouse olfactory epithelium and vomeronasal organ after colchicine treatment.

The cytotoxic agent colchicine induced apoptotic cell death in the mouse olfactory epithelium and vomeronasal organ. The terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling (TUNEL) method revealed the presence of many apoptotic bodies in the middle to basal region of the septal olfactory epithelium and vomeronasal organ near the boundary of the respiratory epithelium at 1 day after intraperitoneal (i.p.) injection of colchicine (4 mg/kg). In some areas of the nasal turbinates, massive apoptosis was observed in the olfactory epithelium. Electron micrographs showed that immature olfactory cells and globose basal cells were killed by the colchicine and had been phagocytized by the supporting cells and macrophages. In some areas of the nasal turbinates, mature olfactory cells were also killed, and thus only the supporting cells and horizontal basal cells remained in the epithelium. Bromodeoxyuridine (BrdU) labeling showed that regeneration occurred in the septum and vomeronasal organ at 4-6 days after colchicine treatment; however, there were no regenerated olfactory cells in some areas of the turbinates up to 30 days after colchicine treatment.

Animals↗
PubMed2001

Colchicine induced rhabdomyolysis.

A case of colchicine induced rhabdomyolysis is reported. A 73 year old man with ischaemic heart disease, atrial fibrillation, chronic congestive cardiac failure, and chronic gout presented with diffuse muscle pain. He had been taking an increased dose of colchicine (1.5 mg daily) for an exacerbation of gout for six weeks before the presentation. Investigations confirmed the diagnosis of rhabdomyolysis and discontinuation of colchicine resulted in resolution of clinical and biochemical features of rhabdomyolysis. Although neuromuscular adverse effects of colchicine are well recognised, rhabdomyolysis is rare and this is only the fourth reported case of colchicine induced rhabdomyolysis in the literature.

Aged↗
PubMed1979

Effects of colchicine and vinblastine on in vitro gastric secretion.

The effects of colchicine and vinblastine on in vitro bullfrog gastric mucosal preparations were studied with respect to H+ and pepsinogen secretion. In the concentration range of 1--50 mM, an initial but transient colchicine-mediated stimulation of H+ secretion is followed by a dose-dependent inhibition. The transient stimulation of H+ secretion can be confirmed in resting preparations in the absence of added secretagogues. In the same concentration range, colchicine inhibits pepsinogen secretion to a greater degree than H+ secretion. Vinblastine (10(-5)--5 X 10(-4) M) was more effective than colchicine in inhibiting both H+ and pepsinogen secretion. The kinetics of inhibition of secretion by both colchicine and vinblastine were slow. Cytochalasin B had no effect on either secretion.

Animals↗
PubMed1981

Effects of colchicine or cytochalasin B on pulmonary macrophage endocytosis in vivo.

Pulmonary macrophages defend lung surfaces by ingesting deposited particles. We investigated to what extent this uptake of particles can be modulated in vivo by two drugs, colchicine and cytochalasin B (CytB). 198Au colloidal gold, in isotonic saline carrier fluid, was intratracheally instilled into male Syrian golden hamsters. The uptake of these particles by pulmonary macrophages was measured when the carrier fluid contained only colloidal gold and when this test particle was combined with graded doses of either drug. We found that macrophage uptake of the particles 1 h after instillation was depressed 37% when colchicine was added to the instillate (150 micrograms/100 g BW). Depression of particle uptake was also seen with CytB at 15 micrograms/100 g BW. Experiments with tritiated colchicine and CytB showed that both drugs were rapidly cleared from the lungs early in the 1 h phagocytic period. The effect of intravenous colchicine and CytB on the clearance of intravenously injected gold colloid by the liver and spleen reticuloendothelial system was negligible. The results of these experiments, in conjunction with in vitro effects of colchicine and CytB, provide insight into the components of cell function active in particle uptake in situ.

Animals↗
PubMed2002

Colchicine attenuates left ventricular hypertrophy but preserves cardiac function of aortic-constricted rats.

To investigate the effects of colchicine on left ventricular (LV) function and hypertrophy (LVH) of rats subjected to constriction of transverse aorta (TAoC), we evaluated SO (sham operated, vehicle; n = 25), SO-T (sham operated, colchicine 0.4 mg/kg body wt ip daily; n = 38), TAoC (vehicle; n = 37), and TAoC-T (TAoC, colchicine; n = 34) on the 2nd, 6th, and 15th day after surgery. Colchicine attenuated LVH of TAoC-T compared with TAoC rats, as evaluated by ratio between LV mass (LV(M)) and right ventricular mass, LV wall thickness, and average diameter of cardiac myocytes. Systolic gradient across TAoC ( approximately 45 mmHg), LV systolic pressure, LV end-diastolic pressure, and rate of LV pressure increase (+dP/dt) were comparable in TAoC-T and TAoC rats. However, the baseline and increases of LV systolic pressure-to-LV(M) and +dP/dt-to-LV(M) ratios induced by phenylephrine infusion were greater in TAoC-T and SO-T compared with SO rats. Baseline and increases of +dP/dt-to-LV(M) ratio were reduced in TAoC compared with SO rats. TAoC rats increased polymerized fraction of tubulin compared with SO, SO-T, and TAoC-T rats. Our results indicate that colchicine treatment reduced LVH to pressure overload but preserved LV function.

Animals↗
PubMed2002

Colchicine-induced myopathy with normal creatine phosphokinase level in a renal transplant patient.

A case of a renal transplant recipient with colchicine-induced myopathy is presented. He was on colchicine therapy for 10 months. He was hospitalized for investigation of fatigue, severe myalgia in the lower extremities and elevated serum aminotransferase levels. His viral markers and other factors that may cause myalgia and that may increase the serum aminotransferase levels were either normal or negative. Creatine phosphokinase (CK) levels were normal. Electrophysiological findings indicated myopathy and muscle biopsy was consistent with vacuolar myopathy. After withdrawal of colchicine, the symptoms disappeared gradually and serum aminotransferase levels were normalized. We suggest that colchicine myopathy should be taken into account in patients who have been on colchicine therapy and had unexplained myalgia as well as elevated aminotransferase levels even with normal CK levels.

Colchicine↗
PubMed2004

Topical colchicine selection of keratinocytes transduced with the multidrug resistance gene (MDR1) can sustain and enhance transgene expression in vivo.

In gene therapy, a clinically relevant therapeutic effect requires long-term expression of the desired gene at a level sufficient to correct or at least alleviate the underlying gene defect. One approach to achieve persistent as well as high-level transgene expression in a significant percentage of target cells would be to select cells expressing both the desired transgene and a linked selectable gene--such as the human multi-drug resistance (MDR1) gene--in a bicistronic vector. Because of its accessibility, the skin is a very attractive target tissue to select genetically modified cells, allowing topical application of a selecting agent, thus minimizing potential toxic side effects. Among the potential selecting drugs, agents that block cell division, such as colchicine, are of particular interest because the use of anti-mitotic drugs takes advantage of the rapid keratinocyte (KC) turnover in the epidermis and the need for continued proliferation to substitute the KC lost due to selection. Before assessing the therapeutic benefit of such an approach, several key questions need to be answered in preclinical models: (1) Does topical colchicine application achieve the desired in vivo effect by blocking KC mitosis without eliciting unwanted toxic side effects? (2) Are MDR-transduced (MDR+) human KC still able to proliferate and differentiate when treated with colchicine? (3) Can MDR+ KC be enriched by topical selection? (4) Does topical selection result in persistent transgene expression by selecting KC stem cells expressing MDR? To answer these questions and to test the feasibility of such an approach both an in vitro skin equivalent and an in vivo human skin graft model were developed in which MDR+ KC were treated with different dosages of colchicine. Quantitative and qualitative analyses of MDR expression in human KC showed that topical colchicine treatment selects high-level transgene expression in a high percentage of KC. Moreover, determination of transgene copy numbers demonstrated that MDR+ KC progenitor cells were enriched by topical selection resulting in long-term expression of the transgene in the skin. Thus, in summary, these models demonstrate that topical selection of MDR+ KC is a safe approach to efficiently enhance long-term gene expression in the skin and holds future promise for clinical gene therapy applications.

Administration, Topical↗
PubMed1992

Intrahippocampal colchicine alters hypothalamic corticotropin-releasing hormone and hippocampal steroid receptor mRNA in rat brain.

The hippocampus appears to be an important modulator of the negative feedback effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis. It is not known if hippocampal subfields CA1-4 or the dentate gyrus differentially alter gene expression of corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus. We, therefore, examined the effects of selective destruction of dentate gyrus granule cells, which send excitatory glutaminergic inputs to subfields CA4, CA3 and CA2, on CRH expression in the PVN. To determine the possible involvement of steroid receptors in the regulation of CRH expression, we examined the effects of intrahippocampal colchicine on gene expression of the mineralocorticoid (MR; type I) and glucocorticoid (GR; type II) receptors in hippocampal CA fields and dentate gyrus. Colchicine produced a selective loss of dentate gyrus granule cells without affecting pyramidal cells in CA1-4 as early as 1 day after injection; granule cells were completely destroyed after 3 days. CRH mRNA levels were reduced by 38-48% in the PVN 2-14 days after colchicine. MR mRNA levels were decreased in dorsal and ventral CA fields 1-7 days after colchicine. GR mRNA levels were relatively unchanged, showing a slight decrease only in dorsal CA fields on days 2-7. Unexpectedly, CRH was transiently expressed in dorsal and ventral CA fields 1-3 days after colchicine. In the same time period, mRNA levels of inositol 1,4,5-trisphosphate kinase were decreased, suggesting that increases in neural metabolic activity, indicated by this marker, are not responsible for the transient CRH effect. The results suggest that the dentate gyrus is important for maintenance of steroid hormone receptor mRNA levels in the hippocampus and CRH expression in the hypothalamic PVN, and that CRH gene expression is differentially regulated in the hypothalamus and hippocampus.

Adrenocorticotropic Hormone↗
PubMed1985

Preferential nondisjunction of specific bivalents in oocytes from Djungarian hamsters (Phodopus sungorus) following colchicine treatment.

In an attempt to study the mechanisms leading to nondisjunction during meiosis I, Djungarian hamster females were treated with colchicine (3 mg/kg), which binds specifically to tubulin. The number of ovulated oocytes per female was significantly reduced following colchicine treatment (8.2 +/- 5.3, compared to 10.6 +/- 5.9 in controls receiving saline solution only). Application of colchicine rather late during oocyte maturation (ie, 5.5 h after injection of human chorionic gonadotrophin) caused a significant increase in the number of ovulated diploid (34.5%) and hyperhaploid (11.7%) oocytes, compared to the frequencies observed in the saline-treated controls (0.8% and 3.5%, respectively). Specific bivalents (viz, the large meta- and submetacentric chromosomes of groups A, B, and C) were preferentially involved in colchicine-induced nondisjunction. The same pattern of chromosomal malsegregation was previously observed in oocytes from this hamster species following hypergonadotrophic stimulation. Preferential involvement of bivalents in the process of nondisjunction, whether induced by colchicine or hypergonadotrophic stimulation, is explained by an interference with microtubular function affecting those bivalents that are the last to segregate.

Animals↗
PubMed1981

Halothane modifies colchicine binding to tubulin.

Tubulin extracted from rat brains was incubated at 37 degrees C with 3H-colchicine in the presence and absence of 28 mM halothane. The amount of 3H-colchicine bound to tubulin was reduced by nearly 50% at a colchicine concentration of 5 x 10(-5) M when halothane was present. At low (1 x 10(-7) M) and at high (1 x 10(-3) M) concentrations of colchicine, halothane did not affect the binding as much. The inhibition of colchicine-binding to tubulin by halothane appeared to be non-competitive.

Animals↗