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PubMed2006

Liquid chromatography-tandem mass spectrometry for the determination of colchicine in postmortem body fluids. Case report of two fatalities and review of the literature.

Poisoning by colchicine may occur following ingestion of this alkaloid used for the treatment of acute gouty arthritis. The authors report two fatalities and describe a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS-MS) triple-quadrupole method for the determination of colchicine in autopsy samples. One milliliter of heart blood, femoral blood, urine, bile, gastric, and vitreous each were extracted with saturated NH4Cl at pH 9.6 and dichloromethane/5% isopropanol. Separation was achieved on a C18-Xterra column with a mobile phase consisting of 2 mM ammonium formate buffer (pH 3)/acetonitrile in a gradient mode. Four product ions of the protonated molecule were monitored. The method was fully validated in whole blood (1 mL) and was linear in the range of 0.5-50 ng/mL (r2>0.99). The limit of detection was 0.1 ng/mL (50 times S/N), and the limit of quantitation was 0.5 ng/mL with RSDs<11.8% intraday (n=6), <18.7% interday (n=18), and accuracy<3% (n=18). Case #1: a 33-year-old nurse committed suicide by the ingestion of 80 colchicine 1-mg tablets. She died 61 h later after resuscitation procedures. Colchicine was found in heart blood at 5.2 ng/mL, femoral blood at 17.4 ng/mL, urine at 19.4 ng/mL, bile at 42.8 ng/mL, gastric at 348 ng/mL, and vitreous at 3 ng/mL. Case #2: a 57-year-old man with gout was found dead at home. Colchicine was found in heart blood at 22.8 ng/mL, femoral blood at 21.9 ng/mL, lung blood at 45.2 ng/mL, urine at 148.5 ng/mL, bile at 1818.5 ng/mL, gastric at 219.8 ng/mL, and vitreous at 0.5 ng/mL. These results were consistent with death. Because of its good sensitivity, this LC-ESI-MS-MS triple-quadrupole method is suitable for the determination of colchicine not only in fatalities but also for pharmacokinetic studies.

Adult↗

PubMed1988

The use of oral colchicine for low-back pain. A double-blind study.

The use of colchicine for the treatment of low-back pain has been controversial; however, recent studies have shown its effectiveness when used intravenously. Studies using oral colchicine alone are lacking. The purpose of this study is to evaluate in a prospective, double-blind fashion the use of oral colchicine in the treatment of low back pain. Group I patients (15) were treated with a placebo capsule, and Group II (12) patients were treated with a colchicine capsule prescribed in a "burst dose" regimen. Patients were evaluated at 1, 2, 4, 6, and 12 weeks with a mean followup of 12 weeks. Parameters studied included patient characteristics, compliance, the McCoy pain drawings, pain analogue scales, the Million scale and objective tests. In terms of therapeutic response, the study shows no statistically significant difference between oral colchicine and placebo. The colchicine group did have an increased number of side effects.

Administration, Oral↗

PubMed2004

Accidental intravenous colchicine poisoning.

Colchicine is a commonly used drug for the treatment of gout and other indications. Toxicity from intentional oral overdoses of colchicine has been reported. Two cases are reported here in which colchicine was given by intravenous injection, and patients presented with multiorgan toxicity. The authors tested plasma and urine colchicine levels in these patients and found them significantly elevated. Testing of the vial from which the colchicine injections were given showed that the vial was mislabeled and contained 10-fold greater concentration of drug than the labeling indicated. These patients thus received a bolus dose of 20 mg of intravenous colchicine rather than the intended 2-mg dose. An intravenous dose of this magnitude has not previously been reported.

Colchicine↗

PubMed1982

Colchicine-induced modulation of collagenase in human skin fibroblast cultures. I. Stimulation of enzyme synthesis in normal cells.

Microtubule-active agents affect the secretion of a variety of proteins, including collagenase. To gain insight into the mechanisms involved in this process, we examined the effects of colchicine on the synthesis, secretion, and activity of human skin collagenase. When added to monolayer cultures of human skin fibroblasts, 10(-6) M colchicine produced a mean 3-fold increase in trypsin-activatable collagenase in the culture medium. Stimulation was not observed with lumicolchicine. The enhanced accumulation of collagenase was dose-dependent with 10(-9), 10(-8), 10(-7), and 10(-6) M colchicine giving collagenase activities/mg protein that were 100 +/- 6%, 165 +/- 20%, 186 +/- 34%, and 297 +/- 62% of control, respectively. Although the effect on collagenase was seen under conditions independent of cellular growth (i.e., in serum-free medium), maximum stimulation occurred in subconfluent cultures. The colchicine-induced increase in activity was paralleled by an increase in immunoreactive enzyme protein, suggesting stimulation of enzyme synthesis. The catalytic efficiency of the enzyme (activity per unit immunoreactive protein) was unchanged, however, indicating that a structurally normal enzyme was being synthesized. To examine the process in more detail, the biosynthesis of 3H-labeled collagenase was quantitated in these cultures by specific immunoprecipitation. Although 10(-6) M colchicine produced no increase in total protein synthesis, an increased rate of collagenase synthesis was seen after only 1.5 hr. These data suggest that colchicine has a specific effect on the synthesis of collagenase and may be a useful probe for studying its regulation.

Cells, Cultured↗

PubMed1991

Colchicine inhibits acetylcholine receptor stimulation of G protein GTPase activity in rat striatum.

Colchicine, which is known to influence tubulin function, was used to delineate a possible role of tubulin in signal transduction in the rat striatal membranes. Low Km GTPase activity (EC 3.6.1.-) was assayed in 10 micrograms membrane protein using [gamma-32P]GTP at 37 degrees in an ATP-regenerating buffer containing 1 microM unlabeled GTP. At 10 and 100 microM, colchicine inhibited the GTPase activity by 18% and 40%, respectively. Colchicine (100 microM) inhibited the enzymatic activity by 30-40% at all the time points the reaction was monitored. Acetylcholine (ACh) stimulated the low Km GTPase activity in a concentration-dependent manner, by up to 57%. ACh-stimulated activity was accepted as reflecting GTP hydrolysis catalyzed by receptor-coupled transducer G proteins. In the presence of 100 microM colchicine, the ability of ACh to stimulate G protein GTPase activity was inhibited. For example, at 10 microM ACh the enzyme activity was stimulated up to 52%; in the presence of 100 microM colchicine, 10 microM ACh stimulated the activity by only up to 33%. These results suggest that colchicine disrupts ACh receptor-G protein coupling as a result of its interaction with tubulin or G protein(s) or both.

Animals↗

PubMed1991

Colchicine in primary biliary cirrhosis.

Colchicine, which has been used for hundreds of years in the treatment of gout, has found a new use in the treatment of cirrhosis. In the experimental animal, and in vitro, colchicine decreases inflammation, inhibits collagen synthesis and also increases collagen degradation by activating collagenase. Many of the putative beneficial actions of the drug in cirrhosis, as well as its toxic side effects, are due to the fact that it binds to tubulin and thereby disrupts microtubules; however, it is unclear which of these actions, mostly demonstrated in the experimental animal, are present in the doses currently used in man. There have been 4 controlled trials of colchicine in various forms of cirrhosis, three of which have concerned primary biliary cirrhosis. Data are currently available on 146 colchicine-treated patients, of which 92 had primary biliary cirrhosis. Colchicine improves the conventional liver function tests in primary biliary cirrhosis and also reverses the basic defect in hepatic excretory capacity characteristic of this disease. The drug appears to have no significant effect on symptoms, clinical features or liver histology, but in 2 of the 3 primary biliary cirrhosis trials, as in the Mexican study of alcoholic and post-hepatitic cirrhosis, colchicine treatment was associated with improved survival.

Animals↗

PubMed1993

N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)colcemid, a probe for different classes of colchicine-binding site on tubulin.

The nature of binding of 7-nitrobenz-2-oxa-1,3-diazol-4-yl-colcemid (NBD-colcemid), an environment-sensitive fluorescent analogue of colchicine, to tubulin was tested. This article reports the first fluorometric study where two types of binding site of a colchicine analogue on tubulin were detected. Binding of NBD-colcemid to one of these sites equilibrates slowly. NBD-colcemid competes with colchicine for this site. Binding of NBD-colcemid to this site also causes inhibition of tubulin self-assembly. In contrast, NBD-colcemid binding to the other site is characterised by rapid equilibration and lack of competition with colchicine. Nevertheless, binding to this site is highly specific for the colchicine nucleus, as alkyl-NBD analogues have no significant binding activity. Fast-reaction-kinetic studies gave 1.76 x 10(5) M-1 s-1 for the association and 0.79 s-1 for the dissociation rate constants for the binding of NBD-colcemid to the fast site of tubulin. The association rate constants for the two phases of the slow site are 444.4 M-1 s-1 and 11.67 M-1 s-1 [corrected], respectively. These two sites may be related to the two sites of colchicine reported earlier, with binding characteristics altered by the increased hydrophobic nature of NBD-colcemid.

4-Chloro-7-nitrobenzofurazan↗

PubMed2006

Colchicine myoneuropathy in chronic renal failure patients with gout.

Colchicine myoneuropathy is a rare and often underdiagnosed disease. It often presents as painless subacute muscle weakness. We present a case of painful colchicine myoneuropathy in a 76-year-old man with chronic renal failure and gout. Published work about clinical presentations of colchicine myoneuropathy in gouty arthritis patients are reviewed. During the previous year, the patient had a drug regimen of colchicine 0.5 mg three times per day for a 3 day course each month. He developed bilateral lower leg weakness and severe myalgia. His serum creatinine level was 680.7 micromol/L and creatinine kinase was 959 IU/L on admission. Laboratory findings included decreasing amplitude of motor and sensory nerve conduction velocity and an electromyogram showed small amplitude, short duration polyphasic waves over the right biceps. A muscle biopsy disclosed vacuolar changes in the cytoplasm. These results all supported a diagnosis of colchicine myoneuropathy. After cessation of colchicine, the creatinine kinase level decreased approximately 50% in 6 days, myalgia subsided and his muscle weakness improved gradually over the next 2 weeks.

Aged, 80 and over↗

PubMed1983

Effect of colchicine on 45Ca and choline uptake, and acetylcholine release in rat brain synaptosomes.

The effects of 1 and 10 mM colchicine on the K+-evoked release of preformed and newly synthesized acetylcholine and on the K+-depolarization-stimulated uptake of 45Ca were compared in rat brain synaptosomes. Preincubation of synaptosomes with 1 mM colchicine had little effect on transmitter release and on uptake of 45Ca; 10 mM colchicine inhibited both the release of transmitter and uptake of 45Ca by 58%. Since 1 mM colchicine has been shown to disaggregate intrasynaptosomal microtubules almost completely, but to be without effect on release of either preformed or newly synthesized acetylcholine in our experiments, it is concluded that colchicine modifies transmitter release by reducing Ca2+ influx, rather than by its postulated intracellular action on microtubule-mediated transmitter mobilization. In addition, 1 and 10 mM cholchicine significantly inhibited the high-affinity choline uptake in synaptosomes. This hemicholinium-like action of colchicine may contribute to the reduction of transmitter release.

Acetylcholine↗

PubMed1984

Increase of choline acetyltransferase by colchicine in primary cell cultures of spinal cord.

Colchicine (5-10 microM) increased choline acetyltransferase (ChAT) activity 5-10-fold and suppressed acetylcholinesterase (AChE) and glutamate decarboxylase (GAD) activities to 30% and 50%, respectively, of the levels of control cells in mouse spinal cord cells cultured for several days. The synthesis of radiolabeled acetylcholine (ACh) from [14C]choline was also enhanced 4.6-fold, although the uptake of [14C]choline into cells was decreased to 80% of control level. Neither the incorporation of [3H]leucine into protein nor the total amount of protein was increased by colchicine. Vinblastine also increased ChAT activity while cytochalasin B was not effective. Immunochemical titration study revealed that the increase of ChAT activity by colchicine was due to the accumulation of ChAT molecules. Co-culture of spinal cord cells with skeletal muscle markedly stimulated ChAT activity, and the addition of colchicine to the cocultures showed greater than additive effect. These observations indicate that colchicine increases ChAT molecules in a specific manner, that the stimulatory effect of colchicine on ChAT activity is possibly mediated via the interaction with microtubules, and that the increase of ChAT activity is based on a mechanism different from that of co-cultures with skeletal muscle cells.

Acetylcholinesterase↗

PubMed1979

Studies on a morphologically distinct colchicine-resistance variant of Entamoeba sp.

Colchicine has a temperature-dependent cytotoxic effect on Entamoeba sp. (Laredo isolate) that is most apparent when the drug is applied during the initiation of cultures at a concentration of 7.5 mM or higher. Continued transfer of cultures in medium containing progressively increasing concentrations of colchicine has resulted in a variant that grows prolifically in the presence of colchicine (7.5 mM) with a generation time comparable to that of the parent stock, Comparison of a number of parameters of the 2 variants revealed that colchicine resistance was accompanied by a change in cell shape, a reduced membrane permeability, which could partially be overcome by the addition of dimethyl sulfoxide (DMSO), and a reduced tolerance to osmotic stress. However, the parent strain and resistant variant were equally susceptible to cycloheximide and puromycin suggesting that the acquired colchicine resistance may not be explained on the basis of an entirely unspecific generalized reduced ability for drug uptake. Colchicine resistance and altered structure were found to be stable over a long period of time. The possible interdependence of these 2 parameters and their relation to cell motility in Entamoeba sp. are discussed.

Animals↗

PubMed1985

Colchicine effect on bile canalicular motility: long-term study using isolated cultured hepatocytes and time-lapse cinephotomicrography.

The effect of colchicine on spontaneous in vitro contractions of bile canaliculi was assessed using time-lapse cinephotomicrography. Colchicine 2.5 microM and/or taurocholate 5 microM were added to the culture medium. The experiment was long-term, lasting for 13 h. Frame-by-frame analysis revealed that colchicine, after a lag period of 4 h, suppressed the number of contractions over the remainder of the 13-h experimental period, even in the presence of taurocholate (p less than 0.001). The number of contractions per hour decreased in both the colchicine and combined colchicine-plus-taurocholate-treated groups compared to untreated and taurocholate-treated controls. These results do not necessarily mean that colchicine has an effect on the contractile process per se, since the contractions, when they occurred, appeared normal. It is likely that the canalicular motility events are related to bile secretion. The reduction in contractions after a lag period likely indicates that secretion is impaired, and hence the need for contractions is reduced. These results support the view that for normal canalicular bile secretory function, microtubules as well as a normal microfilament system are required.

Animals↗

PubMed1998

Structure-activity analysis of the interaction of curacin A, the potent colchicine site antimitotic agent, with tubulin and effects of analogs on the growth of MCF-7 breast cancer cells.

Originally purified as a major lipid component of a strain of the cyanobacterium Lyngbya majuscula isolated in Curaçao, curacin A is a potent inhibitor of cell growth and mitosis, binding rapidly and tightly at the colchicine site of tubulin. Because its molecular structure differs so greatly from that of colchicine and other colchicine site inhibitors, we prepared a series of curacin A analogs to determine the important structural features of the molecule. These modifications include reduction and E-to-Z transitions of the olefinic bonds in the 14-carbon side chain of the molecule; disruption of and configurational changes in the cyclopropyl moiety; disruption, oxidation, and configurational reversal in the thiazoline moiety; configurational reversal and substituent modifications at C13; and demethylation at C10. Inhibitory effects on tubulin assembly, the binding of colchicine to tubulin, and the growth of MCF-7 human breast carcinoma cells were examined. The most important portions of curacin A required for its interaction with tubulin seem to be the thiazoline ring and the side chain at least through C4, the portion of the side chain including the C9-C10 olefinic bond, and the C10 methyl group. Only two modifications totally eliminated the tubulin-drug interaction. The inactive compounds were a segment containing most of the side chain, including its two substituents, and analogs in which the methyl group at the C13 oxygen atom was replaced by a benzoate residue. Antiproliferative activity comparable with that observed with curacin A was only reproduced in compounds that were potent inhibitors of the binding of colchicine to tubulin. Molecular modeling and quantitative structure-activity relationship studies demonstrated that most active analogs overlapped extensively with curacin A but failed to provide an explanation for the apparent structural analogy between curacin A and colchicine.

Animals↗

PubMed1992

Colchicine prevents tumor necrosis factor-induced toxicity in vivo.

Tumor necrosis factor (TNF) toxicity was induced in vivo by intravenous administration of 15 micrograms of recombinant murine TNF-alpha per kg to galactosamine-sensitized mice. Within 8 h, the animals developed a fulminant hepatitis. Intravenous administration of 0.5 mg of colchicine per kg at 19 and 4 h prior to TNF challenge protected the animals against hepatitis. Lipopolysaccharide (LPS)-stimulated, bone marrow-derived macrophages from C3H/HeN mice released significant amounts of TNF in vitro. When such macrophages were intravenously given to LPS-resistant galactosamine-sensitized C3H/HeJ mice, these animals died within 24 h. Preincubation of these transferred macrophages with colchicine did not suppress the LPS-inducible TNF release from these cells. Concordantly, administration of macrophages exposed to colchicine in vitro resulted in full lethality. However, in vivo pretreatment of C3H/HeJ mice with colchicine 19 and 4 h prior to the transfer of LPS-stimulated macrophages prevented lethality. In LPS-responsive NMRI mice which had been protected against galactosamine-LPS-induced hepatitis by pretreatment with colchicine, TNF was still released into the blood. We conclude from our findings that the in vivo protection by colchicine is mediated by blocking TNF action on target cells while the effector cells of LPS toxicity, i.e., the macrophages, remain responsive.

Animals↗

PubMed1992

Increase of apamin receptors in skeletal muscle induced by colchicine: possible role in myotonia.

We have shown an increase of apamin receptors in rat skeletal muscle membranes following the application of colchicine to the sciatic nerve. 125I-apamin binding to partially purified membrane fractions was observed since day 4, reached a maximum around days 6-15, and was negligible at day 35 after the application of colchicine. Control muscles (nerves treated with buffer solution) showed low binding values (11 fmol/mg protein). Maximal 125I-apamin binding values to partially purified muscle membranes of colchicine-treated rats (42 fmol/mg protein) were lower than those obtained in denervated muscle (95 fmol/mg protein). The affinity binding constant values were 37 (colchicine) and 95 pM (denervation). No signs of muscle denervation were observed on histological examination of the nerve submitted to colchicine treatment nor in the muscles innervated by it. Muscle tension developed by indirect stimulation was the same as in controls. We here show also that partially purified membranes of normal untreated muscles have measurable amounts of 125I-apamin binding (13 fmol/mg protein), similar to those obtained in control muscles. Electromyographic recordings of the muscles after colchicine treatment of the nerve showed abnormal repetitive electrical discharges, similar to myotonic discharges, that were present with a similar temporal course as the increase in apamin receptors. The myotonic-like discharges were suppressed by the topical application of apamin to the muscle, whereas the toxin had no effect on anthracene-9-carbolytic acid-induced myotonia. Our results suggest that a neurotrophic factor that travels by axonal flow is involved in the regulation of the expression of apamin receptors in skeletal muscle membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Increasing inhibition of hepatic protein secretion by colchicine during development.

Colchicine and other antimicrotubular drugs have been shown to impair plasma protein secretion by fetal rat liver at late gestation (day 21) markedly less than by the mature organ. In the present study, the effect of colchicine on plasma protein secretion by liver slices was determined at several times during rat development. Secretion of [14C]leucine-labeled albumin and [3H]glucosamine-labeled glycoproteins was only minimally impaired (20%) by colchicine (50 microM) on gestation day 19. Inhibition of protein secretion increased to about 40% just before birth and remained unchanged throughout the perinatal period. Inhibition increased thereafter until the maximum effect (75%) was first observed 28 days after birth. Studies in which [3H]-colchicine was used indicated that neither reduced colchicine levels in tissue nor reduced affinity of tubulin for colchicine caused the diminished impairment of secretion in immature liver. These findings suggest that participation of microtubules in liver plasma protein secretion is reduced during development and that full participation is delayed beyond the perinatal period in this species.

Animals↗

PubMed1991

Colchicine has opposite effects on interleukin-1 beta and tumor necrosis factor-alpha production.

To study the role of microtubules in cytokine production, the effect of the microtubule depolymerizing agent colchicine on lipopolysaccharide endotoxin (LPS)-induced interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) release by blood monocytes and alveolar macrophages were examined. Immunofluorescence microscopy demonstrated that LPS resulted in the appearance of microtubule-containing cytoplasmic appendages and that colchicine, which resulted in microtubule disruption in monocytes, blocked appendage formation. Colchicine resulted in approximately 50% increase in LPS-induced IL-1 beta release and a 50% decrease in LPS-induced TNF-alpha release by human monocytes at all doses of LPS tested. Although colchicine resulted in a statistically significant increase in LPS-stimulated human alveolar macrophage IL-1 beta release, the increase was not as great as that observed with monocytes. Northern blot analysis suggested that the colchicine effect occurs pretranslationally because colchicine caused an increase in LPS-stimulated IL-1 beta mRNA levels and a decrease in TNF-alpha mRNA levels. These results suggest that microtubules contribute to the regulation of endotoxin-stimulated mononuclear phagocyte cytokine production and that this regulation differs significantly between IL-1 beta and TNF-alpha.

Cells, Cultured↗

PubMed1985

Blockade of colchicine-induced inhibition of vasopressin-stimulated osmotic water flow: failure to influence microtubule formation.

Colchicine inhibits vasopressin-induced osmotic water flow across isolated toad urinary bladder. Concomitantly, colchicine has been shown to reduce the relative cytoplasmic volume fraction of microtubules in the apical granular cells of this epithelium that have been shown previously to mediate the hydroosmotic effect of vasopressin. Therefore, an intact cytoskeleton has been postulated to be a requirement for a full response to vasopressin. Since it has been demonstrated recently that cyclooxygenase inhibitors (meclofenamic acid) abrogate the inhibition by colchicine of vasopressin-stimulated water flow, we tested by stereological criteria the hypothesis that colchicine in the presence of meclofenamic acid does not prevent the polymerization of tubulin. Our results show that the relative cytoplasmic volume fraction of microtubules was reduced 75% by colchicine in the presence or absence of meclofenamic acid. An alternative explanation of the inhibitory action of colchicine is its ability in the toad urinary bladder to enhance the endogenous synthesis of and sensitivity to prostaglandin E, a potent negative modulator of vasopressin-stimulated water flow. An intact microtubular component of the cytoskeleton does not appear to be required for a maximal response to a physiological dose of vasopressin.

Animals↗