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PubMed1982

Effect of colchicine binding on the reversible dissociation of the tubulin dimer.

The reversible subunit-dissociation equilibria of the tubulin alpha beta dimer and of the colchicine-tubulin dimer complex have been examined by equilibrium ultracentrifugation at 4.6 degrees C. The dissociation constants (KD) of tubulin from bovine brain and from flagellar outer-doublet microtubules of the sea urchin Strongylocentrotus purpuratus were 7.4 x 10(-7) M and 15.2 x 10(-7) M, respectively. In contrast, both brain and outer-doublet colchicine-tubulin complexes dissociated less readily into their alpha- and beta-tubulin monomers; KD = 2.7 x 10(-7) M for the brain complex and KD = 5.0 x 10(-7) M for the outer-doublet colchicine-tubulin species. Podophyllotoxin (2 x 10(-4) M), tropolone (10(-4) M), or both podophyllotoxin and tropolone (2 x 10(-4) and 5 x 10(-4) M, respectively) had no effect on the dissociation constant of brain tubulin. Under these experimental conditions, the initial colchicine-binding capacities of brain and flagellar tubulins were 0.87 +/- 0.05 and 0.70 +/- 0.07 mol/mol, respectively. The colchicine-binding activities of free tubulins decayed at 4 degrees C according to first-order kinetics with half-times of 37 h for brain tubulin and 26 h for flagellar tubulin. However, colchicine-tubulin complexes (brain or flagellar) showed no decay of binding activity when stored at 4 degrees C for periods up to 4 days. These results strongly support the following conclusions: (1) colchicine binding induces or stabilizes a conformational isomer of tubulin that dissociates into its alpha and beta monomers less readily than free tubulin; (2) the conformational change in tubulin is specific for binding of the intact colchicine molecule and does not occur when ligands specific for the trimethoxyphenyl subdomain (i.e., podophyllotoxin) or tropolone subdomain of the colchicine-binding site bind singly or simultaneously to tubulin; and (3) bound colchicine stabilizes tubulin against loss of colchicine-binding activity at 4 degrees C. This altered conformation of tubulin may be involved in the substoichiometric poisoning of microtubule assembly produced by the addition of colchicine-tubulin complexes to the ends of microtubules.

Animals↗

PubMed2005

Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival.

BACKGROUND & AIMS: Colchicine improved survival and reversed cirrhosis in several small clinical trials. We compared the efficacy and safety of long-term colchicine, as compared with placebo, in patients with advanced alcoholic cirrhosis. METHODS: Five hundred forty-nine patients with advanced (Pugh B or C) alcoholic cirrhosis were randomized to receive either colchicine 0.6 mg twice per day (n = 274) or placebo (n = 275). Treatment lasted from 2 to 6 years. The primary outcome was all-cause mortality. Secondary outcomes were liver-related morbidity and mortality. Liver biopsy was requested prior to entry and after 24 months of treatment. RESULTS: Attendance at scheduled clinic visits and adherence with study medication were similar in colchicine and placebo groups. Alcohol intake was less than 1 drink per day in 69% of patients. In an intention-to-treat analysis, all-cause mortality was similar in colchicine (49%) and placebo (45%) patients (P = .371). Mortality attributed to liver disease was 32% in colchicine and 28% in placebo patients (P = .337). Fewer patients receiving colchicine developed hepatorenal syndrome. In 54 patients with repeat liver biopsies after 24 or more months of treatment, cirrhosis improved to septal fibrosis in 7 patients (3 colchicine, 4 placebo) and to portal fibrosis in 1 patient (colchicine). CONCLUSIONS: In patients with advanced alcoholic cirrhosis, colchicine does not reduce overall or liver-specific mortality. Liver histology improves to septal fibrosis in a minority of patients after 24 months of treatment, with similar rates of improvement in patients receiving placebo and colchicine. Colchicine is not recommended for patients with advanced alcoholic cirrhosis.

Colchicine↗

PubMed1991

Microtubule-associated proteins-dependent colchicine stability of acetylated cold-labile brain microtubules from the Atlantic cod, Gadus morhua.

Assembly of brain microtubule proteins isolated from the Atlantic cod, Gadus morhua, was found to be much less sensitive to colchicine than assembly of bovine brain microtubules, which was completely inhibited by low colchicine concentrations (10 microM). The degree of disassembly by colchicine was also less for cod microtubules. The lack of colchicine effect was not caused by a lower affinity of colchicine to cod tubulin, as colchicine bound to cod tubulin with a dissociation constant, Kd, and a binding ratio close to that of bovine tubulin. Cod brain tubulin was highly acetylated and mainly detyrosinated, as opposed to bovine tubulin. When cod tubulin, purified by means of phosphocellulose chromatography, was assembled by addition of DMSO in the absence of microtubule-associated proteins (MAPs), the microtubules became sensitive to low concentrations of colchicine. They were, however, slightly more stable to disassembly, indicating that posttranslational modifications induce a somewhat increased stability to colchicine. The stability was mainly MAPs dependent, as it increased markedly in the presence of MAPs. The stability was not caused by an extremely large amount of cod MAPs, since there were slightly less MAPs in cod than in bovine microtubules. When "hybrid" microtubules were assembled from cod tubulin and bovine MAPs, these microtubules became less sensitive to colchicine. This was not a general effect of MAPs, since bovine MAPs did not induce a colchicine stability of microtubules assembled from bovine tubulin. We can therefore conclude that MAPs can induce colchicine stability of colchicine labile acetylated tubulin.

Acetylation↗

PubMed1994

Radioimmunoassay of colchicine with antisera exhibiting variable cross-reactivity.

Colchicine-specific antibodies were produced in either goats or rabbits immunized with three different colchicine haptens conjugated to bovine serum albumin (BSA) at different coupling sites on the three rings of colchicine. Antibodies exhibited a variable cross-reactivity for metabolites and structural analogs of colchicine, which were dependent on the site at which colchicine coupled to the protein carrier. Specificity was also checked on urine samples by separating metabolites using high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA) in tandem. The three antisera presented similar high-affinity constants for colchicine of the order of 10(10) M-1. A sensitive RIA for plasma colchicine was developed with each antiserum. The limit of detection of the three RIAs was 0.2 ng/ml. The inter- and intraassay coefficients were < 13%. RIA was linear up to 8 ng/ml. This RIA procedure was used to study the pharmacokinetics of a single dose of 1 mg oral colchicine in healthy volunteers and the colchicine concentrations of 27 plasma samples from patients on long-term colchicine treatment. No significant differences in plasma colchicine concentrations using the three assays were observed. This RIA procedure appears suitable for plasma colchicine pharmacokinetics and monitoring investigations.

Animals↗

PubMed1975

Colchicine inhibition of stalk elongation in Carchesium sp.: effect of Ca2+ and Mg2+.

The effect of colchicine on stalk elongation in the colonial peritrich ciliate Carchesium sp. has been investigated by growing this protozoon in colchicine-containing media. The length of the stalk in control cultures was 0-4-0-9 mm. In the presence of 2-5-12-5 mM colchicine, stalk elongation was inhibited, and stalk length was inversely proportional to colchicine concentration. At concentrations above 7-5 mM colchicine, stalks measured less than 0-1 mm, and sometimes contained imperfect myonemes. The rate of cell fission was retarded in colchicine-containing media, but nevertheless short-stalked colonies with apparently normal zooids were formed. On transfer of such colonies to media without colchicine normal growth was resumed, but only the newly formed branches were of normal length and contractility. The inhibitory effect of colchicine was annulled by Ca2+ and Mg2+ at 10(-3) and 10(-4) M, respectively. At lower concentrations of Mg2+, but in the presence of Ca2+, the effect of colchicine was less conspicuous than at low Ca2+ concentration in presence of Mg2+. Lowering Mg2+ concentration at low Ca2+ concentration, increased the inhibitory effect of colchicine. It is concluded that colchicine-sensitive, probably tubulin-like proteins, participate in the formation of the contractile stalk of Carchesium. Ca2+ and Mg2+ probably compete with colchicine for a common site in these proteins, or they might reduce the cell's permeability to this drug.

Animals↗

PubMed1979

Treatment of cirrhosis with colchicine. A double-blind randomized trial.

As part of a double-blind, randomized, controlled trial to evaluate the effect of colchicine on liver cirrhosis, 43 cirrhotic patients were assigned to either a placebo (20 patients) or a colchicine (23 patients) treatment group. Colchicine 1 mg and an indistinguishable placebo were administered orally on a daily dose 5 days a week. In the colchicine group, 12 were males and 11 females, while in the control group 13 were males and 7 females. The time elapsed between diagnosis and inclusion in the study was 14.1 mo for the controls and 14.5 mo for the patients on colchicine. Mortality related to the liver disease occurred in 4 patients on colchicine and 8 patients on placebo. Although the probability of surviving in the colchicine group was greater than that of the placebo, the difference did not reach statistically significant levels. Of the colchicine-treated patients, in three a remarkable decrease in liver fibrosis was observed in serial biopsies. In two other patients, carcinoma of the liver developed. Six of the survivors on colchicine have improved clinically, noticing disappearance of ascites and edema, as well as a decrease in the size of the spleen. All the survivors on placebo continue to show clinical deterioration. In contrast to the usual drop of serum albumin seen in the cirrhotic patients, those receiving colchicine increased and maintained their serum albumin levels throughout the study. Serum proline values were elevated only in the alcohol cirrhotic patients. Serum alkaline phosphatase increased only in those patients receiving colchicine. The results indicate that in some cases, liver fibrosis could be modified by treatment with antifibrotic drugs. The use of colchicine at present should remain within controlled studies.

Adult↗

PubMed1982

[Genetic study of stable inheritable cell resistance to colchicine. Chromosomal and hybridization analysis].

The karyotype of mouse B-82CH-9 and B-82CH-9/CAP cell lines as well as the inheritance of their colchicine resistance in somatic cell hybrids were studied. We found earlier that these cell lines differ from other colchicine-resistant mouse and Djungarian hamster cell lines in stability of drug resistance and the lack of overproduction of the p22 polypeptide. The analysis of chromosomes stained by trypsin G-banding technique showed that, unlike mouse L-53 cells possessing unstable colchicine resistance, the B-82CH-9 and its B-82CH-9/CAP derivative had neither chromosomes with long homogeneously staining regions (HSRs) nor other cytological manifestations of gene amplification, such as double-minute chromosomes and small chromatin bodies. The hybrids of B-82CH-9/CAP and sensitive to colchicine Djungarian hamster DM-15 cells appeared in the HAT medium 10-fold more frequently than in the HAT medium containing colchicine. The hybrids grown in the HAT medium had complete chromosome complements of parent cells, while hybrids isolated from the medium with colchicine lacked some Djungarian hamster and mouse chromosomes. 4 independent clones and the cell line originated from the mixture of about 100 clones grown in HAT medium were sensitive to colchicine. We failed to transfer colchicine resistance with B-82CH-9/CAP microcells, while they were able to transfer HPRT+. At the same time, microcells of DM2/1 cells, possessing unstable colchicine resistance connected with gene amplification, could transfer both TK+ and resistance to colchicine. These results indicate that colchicine resistance of B-82CH-9 is suppressed in somatic cell hybrids. Stability of the trait, the absence of cytological manifestations of gene amplification, the lack of overproduction of p22 polypeptide and recessive inheritance suggest that colchicine resistance in these cells is not connected with gene amplification but rather results from another genetic alteration, possibly, gene mutation.

Animals↗

PubMed1995

Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. Results of a prospective, randomized controlled trial.

BACKGROUND AND DESIGN: Cutaneous leukocytoclastic vasculitis is an inflammatory vascular disease with a variable course. There is no defined therapy for this entity. Contradictory data on the effect of colchicine have been reported. To determine the efficacy of colchicine in cutaneous leukocytoclastic vasculitis, 41 patients were randomly selected to receive oral colchicine, 0.5 mg twice daily, or topical emollients. Response to treatment was judged according to the reduction in the number of lesions. After 1 month, in those patients in whom a complete or no response was achieved, therapy was withdrawn; in those with a partial response, treatment was maintained for the following 2 months. At the end of 3 months, treatment was continued only in those patients in whom a relapse occurred. RESULTS: Twenty patients in each group completed 1 month of treatment. One patient taking colchicine dropped out because of diarrhea. At the end of the first month of the study, five patients in the control group and four in the colchicine group achieved a complete response. Nine patients who had a partial response (four in the colchicine group and five in the control group) continued to receive treatment for the following 2 months. Three patients in the colchicine group suffered a relapse after discontinuing therapy but experienced remission with reinstitution of therapy. At the end of the 3 month period, 12 patients in the colchicine group and 10 patients in the control group showed no significant response. Complete response was achieved in five patients in the colchicine group and in seven in the control group. At the 1-year follow-up, 10 patients in each group had no clinical evidence of cutaneous vasculitis. CONCLUSIONS: Colchicine had no significant therapeutic effect in this controlled study. However, the finding that relapse occurred on cessation of colchicine therapy in three complete responders suggests that colchicine can be effective in some patients, despite our negative results.

Administration, Cutaneous↗

PubMedDate not supplied

Intravenous colchicine use in crystal-induced arthropathies: a retrospective analysis of hospitalized patients.

OBJECTIVES: To assess current prescribing patterns, and adherence to recommended practice guidelines, for the use of intravenous colchicine in the treatments of crystal-induced arthropathies. METHODS: Medical records of patients at an urban academic medical center who received intravenous colchicine were reviewed. Information about colchicine dosing and clinical outcomes, with particular attention to interventions by Rheumatologists, was obtained. All hospitalized patients with confirmed or suspected crystal-induced arthropathies treated with intravenous colchicine during a 48-month period were included in this retrospective study. The demographic profile, medical history and clinical data were reviewed. RESULTS: Intravenous colchicine dosing schedules generally followed recommended guidelines. There was no significant difference between patients evaluated by a Rheumatologist, and those that were not, in the cumulative colchicine dose received, clinical response, or length of hospitalization. Relative contraindications to intravenous colchicine were present frequently, but no morbidity or mortality directly attributable to intravenous colchicine was recorded. Patients evaluated by a Rheumatologist prior to receiving intravenous colchicine were significantly more likely to have the diagnosis of a crystal-induced arthropathy confirmed by the identification of crystals from synovial fluid, and less likely to have received oral colchicine prior to intravenous colchicine, than patients who were not evaluated by a Rheumatologist. CONCLUSIONS: Increased involvement of Rheumatologists, and increased awareness of the appropriate indications and guidelines for the safe administration of intravenous colchicine are recommended.

Administration, Oral↗

PubMed2004

Colchicine for primary biliary cirrhosis.

BACKGROUND: Colchicine has been used for patients with primary biliary cirrhosis because of its immunomodulatory and antifibrotic potential. The therapeutical responses to colchicine in randomised clinical trials were inconsistent. OBJECTIVES: To evaluate the beneficial and harmful effects of colchicine in patients with primary biliary cirrhosis. SEARCH STRATEGY: We identified trials through electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials on The Cochrane Library, MEDLINE, EMBASE (September 2003), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing colchicine with any kind of control therapy were included irrespective of language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: The primary outcomes were the number of deaths and the number of death and/or patients who underwent liver transplantation. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence interval (CI). We examined intervention effects by using both a fixed effect model and a random effects model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS: Eleven randomised clinical trials involving 716 patients with primary biliary cirrhosis fulfilled the inclusion criteria. No significant differences were detected between colchicine and placebo/no intervention on the number of deaths (RR 1.21, 95% CI 0.71 to 2.06), the number of deaths and/or patients who underwent liver transplantation (RR 1.00, 95% CI 0.67 to 1.49), liver complications, liver biochemical variables, liver histological measurements, and adverse events. Trial methodology was generally low and some trials had high drop-out rate. A best-worst-case-scenario analysis showed no significant effect of colchicine on mortality (RR 0.59, 95%CI 0.30 to 1.15), while a worst-best-case-scenario analysis showed a significant detrimental effect of colchicine on mortality (RR 2.28, 95% CI 1.17 to 4.44). Colchicine significantly decreased the number of patients without improvement of pruritus (RR 0.75, 95% CI 0.65 to 0.87). However, this estimate was based on only 156 patients from three trials. The effect of the combined treatment with ursodeoxycholic acid was not significantly different from that of colchicine alone. REVIEWERS' CONCLUSIONS: We did not find evidence either to support or refute the use of colchicine for patients with primary biliary cirrhosis. As we are not able to exclude a detrimental effect of colchicine, we suggest that it is only used in randomised clinical trials.

Cholagogues and Choleretics↗

PubMed2006

Colchicine for acute gout.

BACKGROUND: Gout is one of the most common rheumatic diseases worldwide. Colchicine is regarded as beneficial in the treatment of acute gout, but has a high frequency of gastrointestinal adverse events. OBJECTIVES: To evaluate the efficacy and safety of colchicine for relief of the signs and symptoms of acute gouty arthritis, compared to placebo and other treatment interventions. SEARCH STRATEGY: We searched the following electronic databases to March 2006: Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2006), MEDLINE (from 1966), EMBASE (from 1980), CINAHL (from 1982), AMED (from 1985), Web of Science (from 1945) and Current Controlled Trials. SELECTION CRITERIA: Published randomised controlled trials (RCTs) and controlled clinical trials evaluating symptom relief and adverse outcomes of colchicine therapy in acute gout were considered for this review. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened search results for inclusion, collected the data in a standardized form and assessed the methodological quality of the trial using validated criteria. Results for continuous outcome measures were expressed as weighted mean differences. Dichotomous outcome measures were pooled using relative risk. The number needed to treat was calculated for significant outcomes. MAIN RESULTS: One RCT (N=43) comparing colchicine to placebo for the treatment of acute gout was included in this review. The results favour the use of colchicine over placebo with an absolute reduction of 34% for pain and a 30% reduction in clinical symptoms such as tenderness on palpation, swelling, redness, and pain. The number needed to treat (NNT) with colchicine versus placebo to reduce pain was 3 and the NNT to reduce clinical symptoms was 2. All participants treated with colchicine experienced gastrointestinal side effects (diarrhea and/or vomiting) and the number needed to harm (NNH) with colchicine versus placebo was 1. No studies comparing colchicine to NSAIDs or other treatments such as corticosteroids or ACTH were identified. AUTHORS' CONCLUSIONS: Colchicine is an effective treatment for the reduction of pain and clinical symptoms in patients experiencing acute attacks of gout, although in the regimen studied its low benefit to toxicity ratio limits its usefulness. It should be used as a second line therapy when NSAIDs or corticosteroids are contraindicated or ineffective. More evidence is needed to compare the efficacy of colchicine to that of NSAIDs or corticosteroids, the current first line therapy for acute gout.

Colchicine↗

PubMed1992

Effect of cyclosporine on colchicine secretion by a liver canalicular transporter studied in vivo.

The multidrug resistance transport protein is a normal constituent of the liver canalicular membrane, although its function has not been defined in vivo. Colchicine, a multidrug resistance substrate, is eliminated mainly by the liver. Cyclosporine reverses multidrug resistance in vitro, presumably by inhibiting the multidrug resistance transporter. This study assesses biliary colchicine elimination and the effect of cyclosporine on this process. After cyclosporine administration biliary colchicine clearance decreased from 11.6 +/- 0.8 to 2.2 +/- 0.4 ml/min.kg (p less than 0.05), and the colchicine bile/plasma ratio decreased from 166 +/- 9 to 38 +/- 5 (p less than 0.05). Cremophor EL (a cyclosporine vehicle) transiently inhibited biliary colchicine clearance and colchicine bile/plasma ratio, but to a much smaller extent than cyclosporine in vehicle. Biliary cyclosporine clearance was 0.122 and 0.024 ml/min.kg after bolus doses of 2 or 10 mg/kg intravenously, respectively. Cyclosporine bile/plasma ratio was 1.3 to 5.2. When cyclosporine was given 16 hr before colchicine infusion, biliary colchicine clearance decreased 39% (p less than 0.05), and colchicine bile/plasma ratio decreased 51% (p less than 0.05). Thus colchicine is actively secreted into bile and will be useful in the study of the multidrug transporter in vivo. Cyclosporine profoundly inhibits colchicine secretion into bile but is itself mainly metabolized rather than secreted. If competition for a common carrier is the basis for the interaction, then cyclosporine represents a drug that binds to but is not transported by the canalicular transporter.

Animals↗

PubMed1978

Effect of experimental colchicine encephalopathy on brain protein synthesis and tubulin metabolism.

Colchicine blocks axoplasmic flow and produces neurofibrillary degeneration. Brain slices from mice injected intracerebrally with colchicine incorporated more [14C]leucine into protein and had a decreased uptake of [14C]leucine into the perchloric acid-soluble pool than did their controls. Brain RNA content was decreased and free leucine increased by colchicine-induced encephalopathy. The specific activities of proteins from subcellular fractions of colchicine-injected brain were increased in the nuclear fraction, the 100,000-g supernatant, and its vinblastine-precipitable tubulin. The ratio of the specific activity of the crude mitochondrial fraction to that of the total homogenate was decreased, as would be consistent with impaired movement of newly labeled protein into synaptosomes. Colchicine-injected brain extracts contained one or more cytosol fractions that stimulated ribosomal incorporation of [14C]leucine into protein in a cell-free system. Colchicine-binding-activity measurements indicated loss of soluble and particulate tubulin in colchicine-injected brains; the decrease of soluble tubulin was verified by its selective precipitation with vinblastine. Colchicine encephalopathy did not affect the rate of spontaneous breakdown of in vitro colchicine binding activity. Similarities of colchicine encephalopathy to the neuron's response to axonal damage suggest that colchicine-induced increase in protein synthesis may, in part, reflect a neuronal response to blockage of neuroplasmic transport.

Animals↗

PubMed1983

Inhibition by colchicine of human lymphocytotoxic function: dependence on cell-bound drug level, spontaneous reversibility and antagonism by desacetylcolchicine (DAC).

Colchicine elicits inhibition of spontaneous, PHA-dependent and antibody-dependent forms of lymphocytotoxicity of peripheral blood lymphocytes (PBL) against allogeneic target cells. The findings are that it does so in cell-bound form and to near-maximum effect in the amount of this produced in PBL exposed to it at 10(-6)M concentration for 2 h at 37 degrees C. This represents only a small fraction of the cells' binding capacity, which suggests that it involves sites special in kind (localisation) rather than number (occupied at random). Desacetylcolchicine (DAC) (a known inhibitor of the colchicine-tubulin binding reaction) afforded the PBL protection at concentrations that antagonised the binding of colchicine to them. That DAC itself hardly inhibited PBL function is attributed by inference to a weaker binding affinity making for readier loss of it upon removal of the free drug. It did, however, exhibit a tight form of binding to other, functionally-insensitive cell sites not competed for by colchicine at 100-fold higher concentration. Contrary to the impression lent by other workers' studies (on mouse lymphocytes), colchicine-induced suppression of cytotoxic function is not necessarily irreversible. PBL cultured in drug-free medium gradually lost bound colchicine and they recovered in capacity to express spontaneous and PHA-dependent activity, but not in antibody-dependent activity. The residual cytolytic activity shown by colchicine pre-treated PBL appears in the case of antibody-dependent activity to be truly colchicine resistant; it survived unchanged a 10-fold increase in cell-bound drug level and it cannot be explained as a possible product of recovery. This colchicine-independence may reflect the existence of tubulin/microtubule-independent mechanisms contributing to antibody-dependent activity. Examination of colchicine-treated PBL for membrane fluidity changes, using the probe molecule DPH and the technique of fluorescence polarisation, has yielded negative results, even for cells treated at excessively high colchicine concentration (10(-4)M). All three forms of lymphocytotoxic activity were retained in PBL reconstituted after cryopreservation in liquid nitrogen.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1996

Functional, biochemical and anatomical changes in the rat urinary bladder induced by perigangliar injection of colchicine.

The aim of this study was to assess the effect of blocking the axonal transport of sensory neuropeptides, by local injection of colchicine at pelvic ganglia level, on the sensory and efferent functions mediated by capsaicin-sensitive primary afferent neurons innervating the rat urinary bladder. Bilateral injection of colchicine in the prostatic tissue underneath the pelvic ganglia of male rats induced a time-dependent reduction (maximal at 72 h, 100% reduction) of the in vitro contraction of the bladder strips induced by capsaicin (1 microM). The response to electrical field stimulation was also reduced, although to a lesser extent. The direct contractions induced by substance P (100 nM) or KCl (80 mM) were not affected by colchicine pretreatment. In vivo, perigangliar injection of colchicine (72 h before) greatly increased bladder capacity, and reduced the amplitude of micturition contractions and micturition frequency. Capsaicin-induced plasma protein extravasation was abolished in the urinary bladder and reduced in the distal, but not the proximal ureter of colchicine-treated rats. Topical application of capsaicin onto the urinary bladder or onto the stomach induced a cardiovascular pressor reflex in urethane-anaesthetized, spinalized rats. Colchicine pretreatment reduced (by about 50%) the pressor response elicited by chemonociceptive stimulation of the bladder but not that arising from the stomach. Colchicine pretreatment did not produce overt changes of nerve profiles immunoreactive for calcitonin gene-related peptide- or tachykinin-like material in the rat urinary bladder. A more intense staining of nerve fibres positive for calcitonin-gene related peptide-like immunoreactivity and tachykinin-like immunoreactivity was observed in pelvic ganglia of colchicine-pretreated rats. No changes were detected in the dorsal horns of spinal cord segments where pelvic bladder afferents project (L6-S1). Colchicine pretreatment reduced, but did not abolish, bladder levels of substance P-, neurokinin A-, calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity. However, vasoactive intestinal peptide-like immunoreactivity levels were not changed. The capsaicin-evoked (1 microM) release of calcitonin gene-related peptide was abolished in capsaicin as well as in colchicine-pretreated animals. The present findings demonstrate that local treatment of pelvic ganglia with colchicine totally eliminates the "efferent" functions of capsaicin-sensitive afferent nerves in the urinary bladder. Although reduced, tissue levels of sensory neuropeptides are not completely depleted, thus indicating the existence of a releasable versus non-releasable pool. The chemically induced blockade of axoplasmic transport also induces a limited impairment of the sensory function of capsaicin-sensitive afferents, and of the parasympathetic efferent system.

Animals↗

PubMed1997

Colchicine-induced elevation of tissue metallothionein contents is mediated by inflammation-independent serum factor.

Subcutaneous injection of colchicine caused dose-dependent and time-dependent induction of hepatic MT in mice. Other than colchicine, similar MT induction was observed in vincristine- or vinblastine-injected mice, but not in beta-lumicolchicine-injected mice. MT contents were also elevated in the kidney, spleen, lung and heart by colchicine injection. Isoforms of colchicine-induced MT in the liver were identified to be MT-I and II by immunoblot analysis. Unlike turpentine-induced MT synthesis, dexamethasone, an anti-inflammatory agent, could not block the MT-inducing activity of colchicine. Therefore, the MT-inducing activity of colchicine does not appear to be due to inflammation. Mouse serum, obtained at 4-24 h after colchicine treatment, stimulated MT induction in rat hepatoma H4IIEC3 cells. The MT-inducing activity in the serum from colchicine-treated mice was determined to be highest at 12 h after colchicine injection. The MT-inducing activity from sera of colchicine-treated mice was completely blocked by glucocorticoid antagonist, RU38486, similar to such activity in the serum from lipopolysaccharide-treated mice. The ability of sera to induce MT was abolished by heat treatment (56 degrees C, 30 min). The molecular weight of the MT-inducing factor estimated by gel filtration was approximately 20 000 Da. Thus, colchicine-induced stimulation of MT production is mediated by some humoral factor. The production of the MT-inducing factor was not blocked by dexamethasone. We conclude that the mediator is not an inflammatory cytokine or a glucocorticoid and suspect that the disruption of microtubule triggers production or release of such humoral mediator which stimulates MT induction.

Animals↗

PubMed2002

Evaluation of commercial ginkgo and echinacea dietary supplements for colchicine using liquid chromatography-tandem mass spectrometry.

In response to concerns that commercial dietary supplements containing Ginkgo biloba (ginkgo) and Echinacea purpurea, Echinacea angustifolia, or Echinacea pallida (echinacea) might be contaminated with colchicine, a highly selective and sensitive assay was developed for colchicine that is based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS). The method utilizes reversed-phase HPLC separation of compounds in a methanolic extract of the dietary supplement or botanical sample followed by positive ion electrospray ionization with collision-induced dissociation and multiple reaction monitoring of three characteristic fragmentation pathways of the protonated molecule of colchicine, m/z 400 --> 358, 400 --> 326, and 400 --> 310. The minimal detectable concentration of colchicine using this assay was 10 pg on-column, which is equivalent to 20 ppb colchicine in a 0.5 g ginkgo leaf sample. The method was validated by analyzing 0.5 g samples spiked with colchicine and determining the recovery. A total of 26 commercial ginkgo and echinacea dietary supplements were purchased from pharmacies in Chicago, IL, and analyzed for colchicine. In contrast to a recent report, no colchicine was detected in any of the samples. In addition, authenticated ginkgo leaves were collected, assayed, and found to contain no colchicine, which is consistent with the botanical literature. On the basis of the results obtained using this new LC-MS-MS assay, which is more sensitive and more selective than previously published methods for colchicine, we find no cause for concern regarding colchicine contamination of ginkgo or echinacea dietary supplements.

Chromatography, High Pressure Liquid↗

PubMed1983

Inhibition of cardiac proteolysis by colchicine. Selective effects on degradation of protein subclasses.

1. The effect of colchicine (2.5 microM) on cardiac protein turnover was tested with foetal mouse hearts in organ culture. 2. Colchicine had no effect on protein synthesis, but inhibited total protein degradation by 12-18%. Lumicolchicine, which lacks colchicine's ability to disaggregate microtubules, but shares its non-specific effects, did not alter protein degradation. 3. The colchicine-induced inhibition of protein degradation was accompanied by significant changes in cardiac lysosomal enzyme activities and distribution. 4. Colchicine inhibited the degradation of organellar proteins, including mitochondrial cytochromes, more than that of cytosolic proteins. 5. Colchicine decreased the rate of myosin degradation and the rate of proteolysis of the total protein pool to a similar extent. Since the regulation of myosin degradation does not involve lysosomes, this suggests that colchicine affects non-lysosomal as well as lysosomal pathways. 6. Release of branched-chain amino acids from colchicine-treated hearts was disproportionately decreased, suggesting that colchicine increased their metabolism. 7. It is concluded that colchicine, via its actions on microtubules, exerts important inhibitory effects on cardiac proteolysis. Colchicine is especially inhibitory to the degradation of organellar proteins, including mitochondrial cytochromes. Its inhibitory effects may be mediated in part via lysosomal mechanisms, but non-lysosomal mechanisms are probably involved as well.

Amino Acids↗