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PubMed1977

Smooth muscle sensitization induced by colchicine: is it an in vitro property of antitubulin agents?

Colchicine 0.1 microgram/ml induces a reversible increase of guinea-pig isolated ileum contractions (50 to 60% of maximal contractions) to acetylcholine, nicotine and PGE2. At 1 microgram/ml, it induces an irreversible increase of similar contractions to acetylcholine and 5-hydroxytryptamine. Low concentrations of indomethacin are able to reduce or even to abolish this increase. This smooth muscle sensitization could be related to the ability of colchicine to stimulate prostaglandin biosynthesis. Vinblastine has been described to induce a similar in vitro sensitization of guinea-pig isolated ileum. This effect might be also a non-specific property of antitubulin agents. The relationships between such an in vitro sensitization and the clinical effects of colchicine, including diarrhea, remain unclear.

Animals↗
PubMed1993

Effect of antimitotic agent colchicine on carbon tetrachloride toxicity.

A single administration of a subtoxic dose of CCl4 (100 microliters/kg, i.p.) is known to induce hepatocellular regeneration and tissue repair at 6 and 48 h in rats, permitting prompt recovery from the limited liver injury associated with that dose of CCl4. Substantial evidence has accumulated to indicate that the early-phase hepatocellular regeneration and tissue repair are critical for recovery from halomethane hepatotoxicity. The objective of these studies was to test this concept in an experimental framework, wherein a selective ablation of the early-phase cell division should result in prolongation of liver injury followed by recovery. The studies were designed to evaluate the influence of the antimitotic agent colchicine (1 mg/kg, i.p. in saline) on CCl4 toxicity. Colchicine was administered 2 h prior to CCl4 or corn oil injection. Toxicological end points and markers of hepatocellular regeneration were assessed at various time points (2, 6, 12, 24, 48 and 72 h) after the injection of CCl4 to male Sprague-Dawley rats. Hepatocellular injury was assessed through elevations of serum alanine and aspartate aminotransferase and by histopathological examination of the liver. Incorporation of 3H-thymidine in hepatocellular nuclear DNA and mitotic index were used as indices of hepatocellular regeneration. Hepatocellular regeneration stimulated by CCl4 at 2-6 h was blocked by colchicine as evidenced by the decreased 3H-thymidine incorporation and mitotic index,without any significant effect on the second phase of cell division at 48 h. Ablation of this early phase of tissue repair resulted in prolongation of CCl4 hepatoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1977

The effects of colchicine and its derivates on the collagen biosynthesis in vitro.

Recent evidence shows that colchicine decreases collagen production and favourably influences some fibroproductive processes in experimental animal and clinical practice. In our study we investigated the influence of two colchicine derivates--demecolcine and desacetylcolchiceine--on the synthesis of collagen and non-collagen proteins in new born rat skin after the incubation of tissues slices with 14C-proline for 2 h. Collagen was separated in fractions soluble in either 0.45 M NaCl or 2% semi-carbazide that in an insoluble residue. Demecolcine (10(-3)--5.10(-5) M), desacetylcolchiceine (10(-2)--5.10(-4) M), as well as colchicine (10(-4)-10(-6)), inhibited the synthesis of soluble collagen, depending on the drug concentration in the incubation media. Higher concentrations of tested agents also decreased the formation of insoluble collagen. Significant inhibition of non-collagen protein synthesis was ascertained only in the presence of desacetylcolchiceine.

Animals↗
PubMed1975

Effect of colchicine on the secretion of matrices of dentine and enamel in the rat incisor: an autoradiographic study using [3H]-proline.

Effects of colchicine on the incorporation of [3H]-proline into odontoblasts and ameloblasts at various development stages and on the secretion of the radioactive materials from these cells into dentinal and enamel matrices were studied autoradiographically, at 2,4,8 and 24 h after the injection of colchicine. In young functional and functional odontoblasts and ameloblasts, the number of autoradiographic silver grains over the cells increased while those over the matrices decreased 2,4, and 8 h after the injection of colchicine. However, the total number of grains over the cells and matrices were fairly uniform in all stages of cell development at all times after the injection of the drug. It is suggested that the drug does not appreciably affect the incorporation of [3H]-proline or the successive synthesis of the dentinal and enamel matrices but affects the secretion of the matrices in both functional odontoblasts and ameloblasts by interfering with the structure and function of microtubules in these cells.

Ameloblasts↗
PubMedDate not supplied

Pharmacokinetics/bioavailability of colchicine in healthy male volunteers.

In a randomized 2-way cross-over study with twelve healthy male volunteers, two colchicine preparations (tablets, A vs. oral solution, B) were tested. The preparations were administered as single doses of 1 mg; prior to and up to 72 h after medication blood samples were collected and the plasma colchicine concentrations determined. Additionally urine samples were collected at 0-2, 2-4, 4-6, 6-8, 8-10, 10-24, 24-48, 48-72 and 72-96 h intervals. The colchicine plasma and urine concentrations were determined by a newly developed and validated RIA method. The mean area under the plasma concentration-time curve (AUC-1, AUC-3) was calculated as 23.95 +/- 12.10 (AUC-1) and 26.73 +/- 12.75 (AUC-3) h.ng/ml after application of A and 28.01 +/- 14.74 (AUC-1) and 31.57 +/- 16.58 (AUC-3) h.ng/ml after application of B, respectively. Mean peak plasma concentrations of 4.15 +/- 2.35 (A) and 4.88 +/- 3.90 (B) ng/ml were reached at 1.15 +/- 0.38 (A) and 1.13 +/- 0.42 (B) h after application. The mean terminal half-lives accounted for 9.31 +/- 3.98 (A) and 10.57 +/- 5.53 (B) h. The mean total clearance (Cl/F) and volume of distribution (V/F) were found to be 40.12 +/- 20.87 (A) and 46.58 +/- 24.65 (B) l/h and 472.59 +/- 196.46 (A) and 624.89 +/- 304.09 (B) l, respectively. The mean total amount excreted in urine (Ae) was 172.66 +/- 91.51 (A) and 174.85 +/- 63.53 (B) micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

Near fatal acute colchicine intoxication in a child. A case report.

UNLABELLED: An 8-year-old child with familial Mediterranean fever exhibited signs of colchicine intoxication while receiving prophylactic doses of the drug. She developed gastrointestinal, central nervous system, cardiovascular and haematological disturbances. Over 2 months she had been drinking high doses of natural grapefruit juice which, combined with long-term colchicine therapy and a viral upper respiratory tract infection, increased her susceptibility to the drug. CONCLUSION: To the best of our knowledge, this is the first time colchicine intoxication in this age group has been described in the English literature.

Beverages↗
PubMed2004

The effects of colchicine and hydroxychloroquine on the cyclo-oxygenases COX-1 and COX-2.

OBJECTIVE: The aim of this study was to test whether colchicine and hydroxychloroquine have an inhibitory effect on cyclo-oxygenases (COX). METHODS: Measurement of COX-1 and COX-2 activity was performed by using whole blood assay. Serum thromboxane (TXA) and plasma prostaglandin 2 (PGE2) levels were determined using a commercially available enzyme immunoassay kit. Celecoxib, etodolac, and nimesulide were also tested as controls. Since the study was intended to find a qualitative effect rather than a quantitative relationship between the drugs and the enzymes, we used higher concentrations than the therapeutic range. RESULTS: Colchicine did not have an inhibitory effect on cyclo-oxygenases. Hydroxychloroquine had a mild inhibitory effect in a relatively high concentration. As expected, celecoxib, etodolac, and nimesulide did have an inhibitory effect on the cyclo-oxygenases. CONCLUSIONS: Neither colchicine nor hydroxychloroquine exert their anti-inhibitory effect through inhibition of cyclo-oxygenases.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Long-term colchicine therapy in a patient with Behçet's disease and acute promyelocytic leukemia.

Behçet's disease causes a continuous T-lymphocytic mediated inflammatory reaction in the small arterioles, which results in gradual destruction of any human organ or system. The benefit of treatment with colchicine in patients with Behçet's disease has been reported in literature. Acute leukemia has seldom been associated with Behçet's disease, although acute promyelocytic leukemia is a particular subtype of leukemia that is often characterized by special cytogenetic abnormalities. We report a male patient with acute promyelocytic leukemia and Behçet's disease who had received long-term treatment with colchicine. To our knowledge, this is the first report of the concomitant occurrence of acute promyelocytic leukemia and Behçet's disease, which suggests that long-term colchicine therapy has a role in the pathogenesis of acute promyelocytic leukemia. The patient described has been treated with retinoic acid and idarubicin (the ATRA-IDA protocol). At the time of this writing, his disease is in clinical remission.

Adult↗
PubMed2002

Mechanisms of colchicine effect in the treatment of asbestosis and idiopathic pulmonary fibrosis.

The objective of this study was to evaluate the mechanisms of colchicine action in pulmonary fibrosis. The study included 10 patients with pulmonary fibrosis (idiopathic pulmonary fibrosis 5, asbestosis 4, and scleroderma 1) who had been admitted to Bellevue Hospital Center, a tertiary care public hospital in New York City. We administered colchicine 0.6 mg orally for 12 weeks to patients with pulmonary fibrosis. Symptoms, high resolution CT scans, pulmonary function tests, and bronchoalveolar lavage parameters were compared prior to and after treatment. Results showed declines in dyspnea index, selective improvement in several CT scans, but no statistically significant change in BAL cells, cytokines, fibronectin, or hydroxyproline. However, there was a decline in hydroxyproline in the BAL fluid in 8/10 patients. We concluded that colchicine has a mild antifibrotic effect which may be in inhibiting collagen formation since there was no effect on the inflammation that accompanies fibrosis.

Aged↗
PubMed2000

Induction of apoptosis by colchicine in taste bud and epithelial cells of the mouse circumvallate papillae.

Apoptotic cells in the taste buds and epithelia of mouse circumvallate papillae after colchicine treatment were examined by the methods of in situ DNA nick-end labeling, immunocytochemistry, and electron microscopy. After colchicine treatment, numerous positive cells appeared in the taste buds by DNA nick-end labeling, and some epithelial cells in the basal and suprabasal layers in and around the circumvallate papillae also revealed positive staining. Condensed and fragmented nuclei with a high density were occasionally found in the taste bud cells and in the basal and suprabasal layer epithelial cells by electron-microscopic observation. An immunocytochemical reaction for tubulin revealed weak staining in taste bud cells, because of the depolymerization of microtubules, and a decrease of the microtubules in the taste bud cells was observed by electron microscopy. These results indicate that colchicine treatment of mice induces the apoptosis of taste bud and epithelial cells in the circumvallate papillae and dorsal epithelial cells around the circumvallate papillae.

Animals↗
PubMed2003

Efficacy of colchicine therapy in amyloid nephropathy of familial Mediterranean fever.

The aim of this study was to investigate the effect of colchicine therapy on the outcome of amyloid nephropathy of familial Mediterranean fever (FMF) in childhood. The diagnosis of amyloidosis type AA was confirmed by renal biopsy in 38 patients. During a mean follow-up period of 30.5 months (range 6-88 months), the patients received colchicine therapy. While 24 of these patients were compliant with the treatment, 14 patients remained non-compliant. Of the 24 compliant patients, 19 had normal renal function at the onset; in 13 the proteinuria improved, in 5 patients it remained stable, and in 1 patient it deteriorated from a proteinuric to nephrotic stage. Partial resolution of amyloidosis was demonstrated by repeat renal biopsy in 1 patient who showed complete resolution of proteinuria. In contrast, none of 14 non-compliant patients improved, and while only 1 patient was in renal failure initially, 10 patients deteriorated to renal failure during the follow-up period. The presence of tubulointerstitial injury at presentation adversely affected the prognosis. In conclusion, when used appropriately, colchicine can improve proteinuria and prevent chronic renal failure in patients with amyloid nephropathy of FMF. The presence of renal failure or tubulointerstitial injury at presentation and non-compliance with therapy are the factors decreasing the success of therapy.

Adolescent↗
PubMed2005

Neuronal degeneration and iNOS expression in experimental brain contusion following treatment with colchicine, dexamethasone, tirilazad mesylate and nimodipine.

BACKGROUND: The pathophysiological mechanisms of secondary neurological injury after traumatic brain injury are complex. Post-traumatic biochemical reactions include parenchymal inflammation, free radical production, increased intracellular calcium and lipid peroxidation and nitric oxide production. The relative importance of each mechanism is unknown in brain contusions. This study was undertaken to investigate protection by the neuroprotective and/or anti-inflammatory drugs that have different putative mechanisms of action: colchicine, dexamethasone, tirilazad mesylate and nimodipine. METHOD: A brain contusion was produced using a weight-drop model in rats. The animals were treated with either one of the drugs at previously defined relevant dosage or control. Fluoro-Jade labelling, TUNEL-staining and immunohisto-chemistry were used to study neuronal degeneration, cellular apoptosis and iNOS expression. In addition, the number of surviving neurons after 14 days was determined. FINDINGS: The number of degenerating neurons was significantly reduced in all treatment groups at 24 hours while the total number of apoptotic cells including inflammatory cells and glia was unchanged. iNOS-expression was reduced in all treatment groups at 24 hours but not later. Only colchicine and tirilazad mesylate significantly enhanced neuronal survival at 14 days after injury. CONCLUSIONS: The findings underscored that an early neuroprotective effect does not necessarily lead to increased long-term neuronal survival. The absence of a significant long-term effect with nimodipine and dexamethasone agrees with clinical studies. Colchicine with an anti-macrophage/anti-inflammatory activity and the free radical scavenger tirilazad mesylate were effective for amelioration of experimental contusion with moderate energy transfer. Early neuroprotection may to some extent target iNOS via different pathways since all tested drugs affected both iNOS expression and neuronal degeneration.

Animals↗
PubMed2006

Aluminium chloride enhances colchicine production in root cultures of Gloriosa superba.

Root cultures of Gloriosa superba were treated with 5 mM: methyl jasmonate and 125 microM: AlCl3 which enhanced the intracellular colchicine content of the roots by 50-fold and 63-fold, respectively. Ten millimolar of CaCl2 and 1 mM: CdCl2 enhanced biomass significantly (7- to 8.6-fold, respectively) while maximum release of colchicine into the medium was obtained with 10 mM: CdCl2. Casein hydrolysate, yeast extract and silver nitrate had no significant effect on growth and colchicine accumulation in root cultures.

Acetates↗
PubMed1984

The structure of 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone, an effective analog of colchicine.

-Methoxy-5-(2',3',4'-trimethoxyphenyl) tropone is an active analog of colchicine, a mitotic spindle inhibitor, which is missing the middle "B" ring. This compound crystallizes in the triclinic system, space group P1, with Z = 2; a = 10.135(2), b = 10.166 (4), and c = 7.863(2) A; alpha = 82.15(3), beta = 103.49(3), and gamma = 107.16(2); degrees and V = 750.7(4) A. The structure was solved by direct methods and refined by full-matrix least-squares to a final R = 0.063, using 2503 observed reflections and 271 parameters. Despite the absence of the middle ring, the conformation of the molecule is similar to that of colchicine, isocolchicine , and their derivatives. The troponoid ring is dissimilar to the phenyl ring in that it is not aromatic and does have alternating short and long bond lengths. The dihedral angle between the least-squares planes of the two rings is -57.4 degrees. Van der Waals surface representations of the analog and colchicine are presented to demonstrate the similarity and differences of these two molecules . The structural information of the analog is consistent with the interpretation of thermodynamic parameters which govern the interactions between brain tubulin and the analog.

Chemical Phenomena↗
PubMed1992

Sulfhydryl groups of Mimosa pudica tubulin implicated in colchicine binding and polymerization in vitro.

The important characteristic of novel Mimosa pudica tubulin is its ability to bind colchicine only when dithiothreitol is included in the isolation buffer, indicating the involvement of sulfhydryl groups in colchicine binding. Modification of sulfhydryl groups by a sulfhydryl modifying agent also affects the normal assembly of tubulin into microtubules, as revealed by electron microscopic and spectrophotometric studies. The number of free sulfhydryl groups present in tubulin protein responsible for both colchicine binding and polymerization has been found to be 4, distributed in alpha and beta subunits, and is distinctly different from the number reported for animal tubulin.

Binding Sites↗
PubMed1993

Fura-2 transport in toad urinary bladder epithelium: effects of antidiuretic hormone, colchicine and osmotic gradients.

Fluorescence is transferred across the toad urinary bladder when fura-2/AM is added to the mucosal or serosal sides of the epithelium. It was now observed that: (1) Oxytocin (20 nM, serosal) increased fluorescence transfer from the mucosal to the serosal but not from the serosal to the mucosal baths. The ratio between the fluorescence intensities recorded with excitation wavelengths of 340 and 380 nm indicates that the calcium sensitive probe (free fura-2) was transferred to the serosal but not to the mucosal compartment by an oxytocin sensitive transport. (2) Preincubation with probenecid did not change fluorescence transfer in basal conditions but significantly reduced the oxytocin induced increase in free fura-2 transport. (3) Fluorescence accumulation inside the tissue was strongly reduced by oxytocin, but only when fura-2/AM was added to the mucosal side. (4) An osmotic gradient, in the presence of oxytocin, further increased the transfer of fluorescence at 380 nm but not at 340 nm. This indicated that the transfer of a calcium-insensitive fraction was being stimulated. (5) Preincubation with colchicine strongly inhibited fluorescence transfer across the tissue, at both 340 and 380 nm (the 340/380 ratio did not change). (6) Tissue accumulation was increased by colchicine. (7) Vanadate did not inhibit fura-2 transfer in the toad urinary bladder. We conclude that intracellularly-generated free fura-2 is only transported across the basolateral border, and that this transfer is stimulated by ADH. The calcium-insensitive fraction is transferred by a temperature-dependent process, sensitive to an osmotic gradient and colchicine.

Animals↗
PubMed1975

Colchicine-induced inhibition of plasma lipoprotein lipase release in the intact rat.

The release of plasma lipoprotein lipase by heparin was studied in fed and food-deprived rats pretreated with colchicine and vinblastine. Four hours after the administration of either drug the lipoprotein lipase activity released by heparin was only half of that found in controls. Colchicine affected the release of both protamine-sensitive and protamine-resistant lipoprotein lipase. It is suggested that colchicine and vinblastine interfere with the transport of lipoprotein lipase from the site of its storage to the vascular cell surface.

Animals↗
PubMed1981

Colchicine binding in the rat tapeworm, Hymenolepis diminuta.

A fraction with enriched colchicine-binding properties prepared from Hymenolepis diminuta was found to possess many of the properties of tubulin isolated from other sources. Colchicine was bound by a simple saturable process with a dissociation constant of 13.2 microM. The binding capability decayed with a half-life of about 5 h. Binding was unaffected by lumicolchicine, was competitively inhibited by podophyllotoxin (inhibition constant of 4.8 microM) and showed an apparent stimulation by vinblastine sulphate. Sodium chloride also appeared to stimulate the binding process. The ligand/receptor complex had a molecular weight of approx. 112 000 as determined by gel filtration. On the basis of this biochemical and pharmacological evidence it was concluded that the colchicine receptor in the supernatant fraction of the H. diminuta homogenate was almost certainly tubulin. Refinement of the preparation should facilitate further studies on the mode of action of certain types of anthelmintic compound.

Animals↗