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PubMed2000

Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis.

AIM: To establish the efficacy of combination therapy with ursodeoxycholic acid (UDCA) and colchicine in patients with symptomatic primary biliary cirrhosis (PBC), defined by the presence of liver cirrhosis, pruritus or bilirubin exceeding 2 mg/mL. METHODS: A total of 90 patients were randomly assigned to ursodeoxycholic acid 500 mg/daily plus placebo (UDCA group, n=44), or ursodeoxycholic acid at the same dosage plus colchicine, 1 mg/daily (UDCA/C group, n=46). The two groups were comparable for age, sex, stage of disease, severity of pruritus, bilirubin, and Mayo score. All patients underwent clinical, ultrasonographic, and biochemical examinations at entry and then every 6 months up to 3 years of follow-up. Patients with cirrhosis underwent endoscopy every 12 months. In a sub-group of patients without cirrhosis, who consented, liver biopsy was repeated at the end of the study. RESULTS: The number of treatment failures (i.e. dead, orthotopic liver transplantation (OLT), complications of cirrhosis, doubling of bilirubin, untreatable pruritus) was 11 (25%) in the UDCA group and four (9%) in the UDCA/C group (P < 0.05). No significant differences were observed in terms of improvement of liver enzymes related to cholestasis and cytolysis and of amelioration of pruritus. The Mayo score values increased less above the baseline values at 24 and 36 month-intervals in the UDCA/C group than in the UDCA group. Histological evaluation at baseline and at the end of the study was available for 15 patients with pre-cirrhotic stage. A significant reduction in histological grading score was observed in patients from the UDCA/C group, whereas no changes in these histological scores were observed in the UDCA group. CONCLUSIONS: The addition of colchicine to ursodeoxycholic acid in patients with symptomatic primary biliary cirrhosis results in a small but significant reduction of disease progress.

Adult↗
PubMed1992

[Toxic myopathy with kidney failure as a colchicine side effect ifn familial Mediterranean fever].

A 24-year-old woman with familial Mediterranean fever (FMF) had for one year been treated with colchicine, 1 mg daily, for repeated bouts of fever, abdominal pain and arthritis. She was also known to have renal amyloidosis. Lately she had developed gastrointestinal symptoms, muscle pain and obvious, predominantly proximal muscular weakness in both legs. The cause of the symptoms was rhabdomyolysis with an increased creatinine activity of 1000 U/l and marked myoglobinuria (1600 micrograms/l), as well as renal failure with normal uric acid and a creatinine clearance of 3 ml/min per 1.73 m2. Serum creatinine concentration was 970 mumol/l, urea 34 mmol/l. Muscle biopsy corresponded to a subacute necrotizing myopathy with vacuole formation, signs typical of toxic damage. Renal biopsy confirmed advanced amyloidosis. The colchicine dose was reduced to 0.5 mg/d. The renal failure responded to conservative treatment. The myopathy symptoms receded within 4 weeks, creatinine clearance rising to 25 ml/min per 1.73 m2. 12 months after reduction of the colchicine dose the patient was without any FMF-related symptoms.

Acute Kidney Injury↗
PubMed1987

Colchicine myopathy and neuropathy.

Although colchicine has been used for centuries, its neuromuscular toxicity in humans is largely unrecognized. In this report we describe a characteristic syndrome of myopathy and neuropathy and present 12 new cases of the condition. Colchicine myopathy may occur in patients with gout who take customary doses of the drug but who have elevated plasma drug levels because of altered renal function. It usually presents with proximal weakness and always presents with elevation of serum creatine kinase; both features remit within three to four weeks after the drug is discontinued. The accompanying axonal polyneuropathy is mild and resolves slowly. Electromyography of proximal muscles shows a myopathy that is marked by abnormal spontaneous activity. Because of these features, colchicine myoneuropathy is usually misdiagnosed initially, either as probable polymyositis or as uremic neuropathy. The myopathy is vacuolar, marked by accumulation of lysosomes and autophagic vacuoles unrelated to necrosis or to the mild denervation in distal muscles. The morphologic changes in muscle suggest that the pathogenesis involves disruption of a microtubule-dependent cytoskeletal network that interacts with lysosomes. Correct diagnosis may save patients with this disorder from inappropriate therapy.

Action Potentials↗
PubMed1978

Inhibition by colchicine of changes in amino acid transport and initiation of DNA synthesis in regenerating rat liver.

The uptake of amino acids (measured with alpha-aminoisobutyric acid) by hepatocytes stimulated to proliferate by partial hepatectomy followed a biphasic pattern, with an initial peak 8-10 hr after surgery followed by a release of amino acids between 10 and 16 hr and a further increase between 16 and 20 hr after the operation. The second period of increased uptake coincided with the increase in DNA synthesis by the hepatocytes. Colchicine, and other microtubule disrupters administered at the time of partial hepatectomy, abolished the first period of increased amino acid uptake and prevented the cells from initiating DNA synthesis. Pulse-labeling experiments with alpha-aminoisobutyric acid revealed that colchicine did not inhibit amino acid transport per se, but prevented the increased capacity for amino acid transport induced by partial hepatectomy. An injection of colchicine 14 hr after hepatectomy prevented the release of amino acids by the liver and also substantially reduced the initiation of DNA synthesis. The data suggest that the microtubules may play a role in proliferative activation and also in the initiation of DNA synthesis of hepatocytes in vivo and that changes in amino acid transport are linked to these microtubule-requiring processes.

Amino Acids↗
PubMed1979

Differential effects of colchicine and cytochalasins on the shedding of murine B cell membrane IgM and IgD.

Lactoperoxidase (EC 1.11.1.7) catalyzed cell surface radioiodination was employed to monitor the fate of murine B cell membrane (mem) IgM and IgD on radiolabeled cells in short-term culture. Both mem-IgM and mem-IgD were shed from the cell surface with biphasic kinetics. The rapid phase of mem-IgD shedding was somewhat slower (half-time = 12 hr) than that of mem-IgM shedding (half-time = 7-8 hr). The effect of temperature, colchicine, and cytochalasin on the shedding of the two membrane immunoglobulin isotypes was determined. The shedding of mem-IgD was more energy dependent than that of mem-IgM and was sensitive to colchicine but not cytochalasin. Conversely, the shedding of mem-IgM was sensitive to cytochalasin but not colchicine. The results suggest that the mechanisms of shedding of mem-IgM and mem-IgD are qualitatively distinct and may be regulated by microfilaments or microtubules, respectively.

Animals↗
PubMed1980

Preferential neurotoxicity of colchicine for granule cells of the dentate gyrus of the adult rat.

Injections of 5-7 microgram (6-9 nmol) of colchicine into the dentate gyrus of the hippocampus of mature rats result in widespread destruction of dentate granule cells with little, if any, damage to other cell populations, including hippocampal pyramidal cells. Selective destruction of dentate granule cells is also observed after intraventricular injections. The destructive effects of colchicine appear as soon as 12 hr after the injection and lead to the disappearance of the granule cells over a period of days. Whereas the effects on nongranule cell populations in the hippocampus appear to be reversed by approximately 11 days after injection, the granule cells are almost completely absent at long intervals after injection. At the long postinjection survival intervals the disappearance of the granule cells is accompanied by elimination of their terminal projections, the mossy fibers, as revealed by Timm staining for heavy metals. Because the preferential neurotoxic effects of colchicine do not result in morbidity or obvious behavioral debilitation, the toxicity may prove useful for studying the functional consequences of removing specific cell populations in the central nervous system.

Animals↗
PubMed1980

A colchicine-sensitive uptake system in Morris hepatomas.

The interference of microtubular disruptors with the uptake of amino acids and other low molecular weight substrates has been studied in Morris hepatomas, host liver, and regenerating liver. Colchicine inhibits amino acid transport (alpha-aminoisobutyric acid, L-methionine, and L-leucine) in hepatomas by 59-98% whereas transport in host and regenerating liver is not impeded but increased. In hepatomas, treatment urea, and carbonate. Vinblastine, but not lumicolchicine or cytochalasin B, is an effective inhibitor. The inhibition of uptake is not linked to a decrease of cellular ATP and UTP. The data suggest that the transport of low molecular weight substrates in hepatomas is related to microtubules or other colchicine-binding structures, e.g., of the plasma membrane. This colchicine-sensitive uptake system in hepatomas may be due to the malignant transformation of hepatocytes.

Amino Acids↗
PubMed1991

Expanded distribution of mRNA for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the rat brain after colchicine treatment.

The effect of intracerebroventricular injection of the mitosis inhibitor colchicine on expression of mRNA for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 was studied in the rat brain with in situ hybridization. Colchicine up-regulates mRNA for NGF and BDNF in many of the neuronal systems normally expressing these factors. In addition, after colchicine treatment NGF and BDNF mRNAs were localized in several brain areas where they normally cannot be detected. Thus, NGF mRNA was present, for example, in many motor nuclei and in the basal forebrain, and BDNF mRNA was seen in many nuclei in the brain stem and in catecholamine neurons, including dopamine neurons in the substantia nigra. The latter neurons have recently been shown to be sensitive to BDNF, and the present results show that these neurons can produce this factor themselves. A decrease in mRNA for BDNF and neurotrophin 3 was seen only in the granular-cell layer of the hippocampal formation. A strong hybridization signal for BDNF and neurotrophin 3 mRNA was also observed over several myelinated tracts in treated rats, supporting the hypothesis that glial cells as well as neurons can produce these trophic factors.

Animals↗
PubMed1991

Direct photoaffinity labeling of tubulin with colchicine.

Ultraviolet irradiation of the [3H]colchicine-tubulin complex leads to direct photolabeling of tubulin with low but practicable efficiency. The bulk (70% to greater than 90%) of the labeling occurs on beta-tubulin and appears early after irradiation, whereas alpha-tubulin is labeled later. The labeling ratio of beta-tubulin to alpha-tubulin (beta/alpha ratio) is reduced by prolonged incubation, prolonged irradiation, urea, high ionic strength, the use of aged tubulin, dilution of tubulin, or large concentrations of colchicine or podophyllotoxin. Glycerol increases the beta/alpha ratio. Limited data with [3H]podophyllotoxin show that it covalently bound with a similar beta/alpha distribution. Vinblastine, on the other hand, exhibits preferential attachment to alpha-tubulin. The possibilities that colchicine binds at the interface between alpha-tubulin and beta-tubulin, that the drug spans this interface, and that both subunits may contribute to the binding site are suggested.

Affinity Labels↗
PubMed1993

Localization of the colchicine-binding site of tubulin.

We have previously shown that rat brain tubulin, a heterodimer consisting of an alpha and beta monomer, can be covalently labeled with [3H]colchicine by near UV irradiation. Most of the label appears in beta-tubulin. We show here that beta-tubulin can be separated and purified from SDS preparative gels and analyzed by proteolysis. Chymotrypsin yielded a labeled approximately 4-kDa band that contained two peptides. Tryptic digestion also yielded an approximately 4-kDa band containing two peptides. Sequence analysis revealed a peptide of residues 1-36 and 213-242 for chymotrypsin and a peptide of residues 1-46 and 214-241 for trypsin. To identify which peptide carried the label, limited hydrolysis of beta-tubulin was done with trypsin; this procedure yielded a labeled 16-kDa N-terminal peptide and a 35-kDa C-terminal peptide, as identified by antibodies. Isolation of these peptides and extensive digestion with trypsin yielded two labeled peptides corresponding to residues 1-46 from the 16-kDa N-terminal fragment and residues 214-241 from the 35-kDa C-terminal fragment. These results show that at least two regions in beta-tubulin are specifically involved in colchicine binding and that the span of the colchicine molecule, < or = 11 A, bridges these two regions in the native beta monomer.

Animals↗
PubMed1994

2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site.

A metabolite of estradiol, 2-methoxyestradiol (2ME), inhibits angiogenesis in the chicken embryo chorioallantoic membrane assay. Since 2ME causes mitotic perturbations, we examined its interactions with tubulin. In our standard 1.0 M glutamate system (plus 1.0 mM MgCl2 at 37 degrees C), superstoichiometric concentrations (relative to tubulin) of 2ME inhibited the nucleation and propagation phases of tubulin assembly but did not affect the reaction extent. Although polymer formed in the presence of 2ME was more cold-stable than control polymer, morphology was little changed. Under suboptimal reaction conditions (0.8 M glutamate/no MgCl2 at 26 degrees C), substoichiometric 2ME totally inhibited polymerization. No other estrogenic compound was as effective as 2ME as an inhibitor of polymerization or of the binding of colchicine to tubulin. Inhibition of colchicine binding was competitive (Ki, 22 microM). Thus, a mammalian metabolite of estradiol binds to the colchicine site of tubulin and, depending on reaction conditions, either inhibits assembly or seems to be incorporated into a polymer with altered stability properties.

2-Methoxyestradiol↗
PubMedDate not supplied

Does smoking change the efficacy of combination therapy with vitamin E and colchicines in patients with early-stage Peyronie's disease?

This study was conducted to find out if smoking has an effect on the results of combination therapy with vitamin E and colchicines in patients with early-stage Peyronie's disease (PD). A total of 58 potent patients suffering from early-stage PD were included in the study (mean age 47.3 years, range 25-73 y). The time from onset of the disease was <6 months and no patient had ED. The patients with severe fibrotic or calcified plaques were not included in the study. Of the patients, 36 were smokers (Group 1) and 22 were non-smokers (Group 2). All the patients received vitamin E (800 IU daily) and colchicines (1 mg daily) for 6 months. Follow-up ranged from 5 to 13 months (mean 10.3 m). The combination therapy was effective and well tolerated in both groups. There were no significant differences between the two groups according to age, disease duration, related disease (diabetes, hypertension, hypercholesterolemia, and hypertriglyceridemia), plaque sizes, and plaque numbers. The resolution in pain and increase in penile curvature and plaque size were similar rates in both groups (p > 0.05), while decrease in penile curvature and plaque size were higher in Group 2 (p < 0.05). No patient discounted the therapy due to side effects. The oral combination therapy with vitamin E and colchicines appears to be an effective procedure in patients with early-stage PD and smoking may have worsening effects on the treatment results.

Adult↗
PubMed1991

Treatment with intravenous colchicine.

This article studies 27 patients with resistant temporomandibular related symptomatology. It evaluates them comparing both their dental and medical diagnosis after the treatment with intravenous and oral colchicine. Modern medicine has used this drug in the treatment of gouty arthritis. It is, however, the oldest medication used in recorded history. Colchicine is a potent drug with potential side effects. Intravenous colchicine's major complication is the possible painful chemical burn to the injection site which may occur if the drug extravasates from the vein.

Colchicine↗
PubMed1999

Interest of colchicine for the treatment of cystic fibrosis patients. Preliminary report.

Cystic fibrosis (CF) lung disease is characterized by persistent inflammation. Antiinflammatory drugs, such as corticosteroids and ibuprofen, have proved to slow the decline of pulmonary function although their use is limited because of frequent adverse events. We hypothesized that colchicine could be an alternative treatment because of its antiinflammatory properties and upregulatory effect on cystic fibrosis transmembrane regulator (CFTR) closely related proteins. We herein present results obtained in an open study of eight CF children treated with colchicine for at least 6 months. Clinical status was better in all patients and respiratory function tests significantly improved in five. Median duration of antibiotherapy decreased significantly. These preliminary results support our hypothesis of a beneficial effect of colchicine in CF patients and stress the need for a controlled therapeutic trial.

Adolescent↗
PubMed1974

The effects of parathyroid hormone, colchicine, and calcitonin on the ultrastructure and the activity of osteoclasts in organ culture.

The ultrastructure of osteoclasts was examined in fetal rat bones after stimulation or inhibition of resorption in culture. A central ruffled border area completely encircled by a clear zone was considered to represent the resorbing system of the cell. The proportion of ruffled border and clear zone in osteoclast cross sections was compared with changes in bone resorption as measured by the release of previously incorporated radioactive calcium ((45)Ca). In control cultures 55% of the osteoclast cross sections showed an area closely apposed to bone and this consisted mainly of clear zone; only 11% showed ruffled borders. Treatment with parathyroid hormone (PTH) increased (45)Ca release, increased the frequency of finding areas closely apposed to bone (79%), and markedly increased the frequency of the ruffled border area (64%). Colchicine given concurrently with PTH decreased the number of osteoclasts. Colchicine or calcitonin treatment after PTH stimulation decreased the proportion of ruffled border area significantly by 1 h; this was followed by a decrease in (45)Ca release. These inhibited osteoclasts resembled osteoclasts from control, unstimulated cultures, suggesting that the cells had returned to their inactive state. Colchicine-treated osteoclasts also showed a loss of microtubules and a massive accumulation of 100 A filaments, suggesting that synthesis of microtubular subunits had increased.

Animals↗
PubMed1974

Effects of colchicine, cytochalasin B, and 2-deoxyglucose on the topographical organization of surface-bound concanavalin A in normal and transformed fibroblasts.

The distribution of surface-bound concanavalin A on the membranes of 3T3, and simian virus 40-transformed 3T3 cultured mouse fibroblasts was examined using a shadow-cast replica technique with a hemocyanin marker. When cells were prefixed in paraformaldehyde, the binding site distribution was always random on both cell types. On the other hand, labeling of transformed cells with concanavalin A (Con A) and hemocyanin at 37 degrees C resulted in the organization of Con A binding sites (CABS) into clusters (primary organization) which were not present on the pseudopodia and other peripheral areas of the membrane (secondary organization). Treatment of transformed cells with colchicine, cytochalasin B, or 2-deoxyglucose did not alter the inherent random distribution of binding sites as determined by fixation before labeling. However, these drugs produced marked changes in the secondary (but not the primary) organization of CABS on transformed cells labeled at 37 degrees C. Colchicine treatment resulted in the formation of a caplike aggregation of binding site clusters near the center of the cell, whereas cytochalasin B and 2-deoxyglucose led to the formation of patches of CABS over the entire membrane, eliminating the inward displacement of patches observed on untreated cells. The distribution of bound Con A on normal cells (3T3) at 37 degrees C was always random, in both control and drug-treated preparations. Pretreatment of cells with Con A enhanced the effect of colchicine on cell morphology, but inhibited the morphological effects of cytochalasin B. The mechanisms that determine receptor movement and disposition are discussed.

Agglutination↗
PubMed1975

Inhibition by colchicine of fibrinogen translocation in hepatocytes.

In the rat, 8 h after intraperitoneal administration of colchicine, fibrinogen (detected by antirat fibrinogen antibodies labeled with peroxidase) accumulated in the lumina of the rough endoplasmic reticulum of the hepatocytes; 16 and 24 h after colchicine administration, fibrinogen was detected, respectively, in the lumina of the smooth endoplasmic reticulum and in the Golgi apparatus. The effect of colchicine on the cytoplasmic translocation of fibrinogen could be due to a direct action of the drug on the membranes of the endoplasmic reticulum or could be the indirect result of the disruptive action of the drug on the microtubules.

Animals↗
PubMed1979

Effects of colchicine on endocytosis and cellular inactivation of horseradish peroxidase in cultured chondrocytes.

Horseradish peroxidase (HRP) was used as a marker to study the effects of microtubule-disruptive drugs on uptake and cellular inactivation of exogenous material in cultures of embryonic chick chondrocytes. HRP was ingested by fluid endocytosis, and intracellular enzyme activity subsequently diminished exponentially with time. Cytochemically, reaction product for HRP was found in vesicles often located close to the dictyosomes of the Golgi complex. Colchicine and vinblastine caused disappearance of cytoplasmic microtubules and disorganization of the Golgi complex with concomitant reduction in the cellular uptake of HRP to about half of that in the controls. Lumicolchicine, on the other hand, left cell fine structure and HRP uptake unaffected. These results indicate that microtubules are of considerable importance in the process of fluid endocytosis in cultured chondrocytes although the exact mechanism remains to be elucidated. The rate of intracellular inactivation of ingested HRP was not affected by colchicine or vinblastine. Double-labeling experiments with colloidal thorium dioxide and HRP likewise indicated that fusion of endocytic vesicles and lysosomes is not dependent on intact microtubules. The total specific activities of the three lysosomal enzymes examined were weakly or not at all changed by treatment of the cultures with colchicine or vinblastine. It therefore seems unlikely that microtubular organization plays an important role in the production or degradation of lysosomal enzymes in cultured chondrocytes.

Acetylglucosaminidase↗