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PubMed1996

Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation.

Colchicine, which inhibits cell microtubule assembly by preventing polymerization of tubulin monomers, inhibits cell-mediated immune responses and promotes long-term survival of major histocompatibility complex-incompatible renal allografts in rats. Here we evaluated the effect of blocking cell microtubule assembly by colchicine on T cell and endothelial cell adhesion receptors involved in transducing signals for T cell activation. By using immunofluorescence flow cytometry analysis, evidence is presented that colchicine, in a dose-dependent fashion, downregulated L-selectin and leukocyte function-associated antigen-1, but not CD2 and CD44 on the surface of naive human peripheral blood lymphocytes. This effect was confirmed in two subsets of T lymphocytes, namely, CD45RA- and CD45RO-positive cells. However, colchicine did not influence the rapid shedding of L-selectin from T lymphocytes exposed to activating stimuli. Colchicine inhibited expression of interleukin-2 receptor on activated T lymphocytes. This effect was observed when T lymphocytes were stimulated with both anti-CD3 and anti L-selectin monoclonal antibodies. Colchicine also inhibited lymphocyte function in vitro as documented by inhibition of the human mixed lymphocyte response in a dose-dependent fashion. Moreover, colchicine downregulated surface expression of intercellular adhesion molecule-1 and E-selectin on activated human umbilical vein endothelial cells. These results indicate that blocking cell microfubule assembly inhibits surface expression of adhesion molecules on T cells and endothelial cells, and provides insights into the complex mechanisms of the action of colchicine in vivo.

Antibodies, Monoclonal↗

PubMed1981

Development of carrageenan pleurisy in the rat: effects of colchicine on inhibition of cell mobilization.

Colchicine produced three effects which modified the acute inflammatory response to carrageenan in the rat pleural cavity: (i) inhibition of neutrophil mobilization and concomitant exudate formation (3 hr); (ii) inhibition of monocyte mobilization (21 hr); and (iii) augmented exudate formation (3 and 21 hr). The 1st effect was related to the intraperitoneal dose of colchicine and occurred only at leukopenic dose levels This effect could not be produced by intrapleural injection of nonleukopenic doses of colchicine. The second effect, on the other hand, was produced by intraperitoneal leukopenic doses and to a lesser extent by intrapleural administration of nonleukopenic doses of colchicine. Importantly, the normal biphasic exudative response to carrageenan developed fully in the absence of monocytes. The third effect, a dose-dependent augmentation of both exudative phases of carrageenan pleurisy, was produced by low, nonleukopenic, intrapleural doses of colchicine. The augmented exudate was sensitive to prostaglandin synthetase inhibitors but not to anti-inflammatory steroids. Neither neutrophils nor monocytes were responsible for the augmented exudate. Colchicine, injected into the rat hindlimb or pleural and peritoneal cavities did not elicit the mobilization of neutrophils or a pleural effusion. In addition, colchicine did not affect the magnitude, temporal development, or decay of the potent edematogenic action of serotonin in the rat hindlimb. Thus irritancy was not responsible for any of the effects of colchicine.

Animals↗

PubMed1999

The effects of colchicine on a Peyronie's-like condition in an animal model.

PURPOSE: We have developed an animal model of Peyronie's disease by injecting transforming growth factor beta (TGF-beta) into the rat penis. Our objective is to study the effects of colchicine on the Peyronie's condition in an animal model. MATERIALS AND METHODS: Thirty-six adult male Sprague-Dawley rats received TGF-beta injections into the tunica albuginea and were divided into two groups (n = 18 each). Rats in the first group were divided into three subgroups (n = 6 each). Each rat in the three subgroups received the following: Subgroup 1 received colchicine, subgroup 2 received ibuprofen, and subgroup 3 received regular water. The rats were euthanized after 6 weeks. Rats in the second group were also divided into three subgroups. These rats received the same treatments as the rats in the first group, but treatments began 6 weeks after TGF-beta injection. These rats were euthanized after 12 weeks. Tunical tissue samples were collected and examined using Hart and trichrome stains, electron microscopy (EM), and western blot analysis for TGF-beta detection. RESULTS: In the first group, the colchicine-treated rats exhibited less collagen deposition and less elastic fiber fragmentation than the untreated or ibuprofen-treated rats. EM confirmed the results and showed normal distribution and shape of both collagen and elastic fibers in the colchicine-treated group. In the second group, the colchicine-treated rats exhibited less crowding of the collagen fibers. However, the elastic fibers remained fragmented and scarce. Western blot analysis showed significant down-regulation of TGF-beta expression (5/6) in the colchicine-treated group after 6 weeks. Down-regulation was observed in only 1/6 in both ibuprofen and non-treated groups. After 12 weeks 2/6, 1/6, and 1/6 rats displayed down regulation in the colchicine treated, ibuprofen treated, and non-treated groups, respectively. CONCLUSION: Early colchicine treatment may suppress a Peyronie's like condition in the rat animal model.

Animals↗

PubMedDate not supplied

Biliary excretion of colchicine in newborn rats.

The 24-hr LD50 of colchicine in newborn rats is 0.24 mg/kg, which is about 1/10 that observed in the adult. The 24-hr LD50 of colchicine was relatively constant in rats over 25 days of age. In an attempt to determine the mechanism of the increased sensitivity of the newborn rat to the toxic action of colchicine, the distribution of 3H after the administration of 3H-colchicine (0.1 mg/kg) was measured in 10- and 35-day-old rats. The concentration of 3H was higher in all tissues of the newborn than the adult after ip administration, suggesting an immaturity in the pathway for colchicine elimination. After iv administration, radioactivity disappeared much more slowly from the plasma of the newborn rat than from the adult. This was due to a lower capacity of the liver of the newborn to concentrate colchicine and to excrete it into the bile. Development of the hepatic excretory mechanism responsible for excretion of colchicine occurred at the same age as did the increase in LD50. These results suggest that colchicine is more toxic in the newborn because the drug remains in the body for a longer time due to immaturity of the liver excretory process.

Age Factors↗

PubMed2004

[Effects of colchicine on synthesis and excretion of cytokines and extracellular matrix by human renal fibroblasts].

OBJECTIVE: Renal interstitial fibrosis is the final common pathway leading to end-stage renal failure for progressive renal disease of various types. The present study was undertaken to add to the knowledge on colchicine's antiinflammatory and antifibrotic properties confirmed by both human and experimental studies. As the main effector cells, fibroblasts have a central role in the pathogenesis of renal fibrosis. This study aimed to investigate the effects of colchicine on the synthesis and excretion of cytokines transforming growth factor-beta1 (TGF-beta1), interleukin-1beta (IL-1beta) and extracellular matrix (collagen III, collagen IV) in human renal fibroblast. METHODS: Various concentrations of colchicine (5.0 micromol/L, 10.0 micromol/L, 20.0 micromol/L, 40.0 micromol/L) were used to pretreat human embryo renal fibroblasts for 1 hour which were cultured in vitro and then stimulated by 10.0 microg/ml of lipopolysaccharide (LPS). After 18 hours, these fibroblasts and their supernatant were collected. The expression of TGF-beta1 mRNA, IL-1beta mRNA in the cells was studied by using RT-PCR, and the excretion of TGF-beta1, IL-1beta, collagen III and collagen IV by the fibroblasts was assessed by ELISA respectively. RESULTS: (1) By pure stimulation with 10.0 micro g/ml LPS, the expression of TGF-beta1 mRNA and IL-1beta mRNA of fibroblasts was up-regulated 3 times (66.1 +/- 1.6 vs. 22.3 +/- 2.0, q = 590.5, P = 0.002) and 4.7 times (22.0 +/- 2.2 vs. 4.7 +/- 0.8, q = 106.8, P = 0.009), respectively. The protein excretion of TGF-beta1 and IL-1beta was remarkably increased as well compared with the control group [TGF-beta1: (516 +/- 14) pg/ml vs. (420 +/- 5) pg/ml (q = 80.3, P = 0.012), IL-1beta: (3.4 +/- 0.3) pg/ml vs. (0.3 +/- 0.1) pg/ml (q = 297.9, P = 0.003)]. (2) Colchicine could inhibit the expression of TGF-beta1 mRNA and protein in a dose-dependent manner. IL-1beta mRNA and protein were both up-regulated by colchicine. (3) LPS could not stimulate the excretion of extracellular matrix by fibroblasts, but the excretion of collagen III and collagen IV was down regulated by colchicine in a dose-dependent manner. CONCLUSION: (1) The expression of TGF-beta1 mRNA and the excretion of TGF-beta1 protein in the fibroblasts was significantly suppressed by colchicine, while the expression of IL-1beta mRNA and the excretion of IL-1beta protein were enhanced. (2) Colchicine has significant inhibitory effect on the excretion of extracellular matrix such as collagen III and collagen IV in fibroblasts.

Colchicine↗

PubMed1991

Colchicine clearance is impaired in alcoholic cirrhosis.

Colchicine may have benefit in primary biliary cirrhosis and alcoholic liver disease. It is currently used in patients with impaired liver function, yet little is known about its elimination in such patients. Colchicine clearance in the rat is significantly impaired in various models of liver disease. To study this in human beings, colchicine pharmacokinetics were compared in normal subjects and patients with alcoholic cirrhosis. Colchicine clearance was impaired in the cirrhotic patients. Normal subjects had a mean clearance of 10.65 +/- 1.82 ml/min.kg, whereas cirrhotic patients had a mean clearance of 4.22 +/- 0.45 ml/min.kg (p less than 0.01). The half-life was 57.4 +/- 14.2 min in control subjects vs. 114.4 +/- 19.7 min in cirrhotic patients (p = 0.054). Volume of distribution was not different in the two groups (0.718 +/- 0.1 L/kg in control subjects; 0.716 +/- 0.158 L/kg in cirrhotic patients, p greater than 0.99). No correlation was seen between colchicine clearance and bilirubin, albumin, prothrombin time or Child-Pugh classification, but this may be the result of the small number of patients studied. Based on the values measured, it is estimated that colchicine steady state would change from an average 1.12 ng/ml in normal individuals to 2.82 ng/ml in the cirrhotic patients if 0.6 mg were taken every 12 hr. It is unknown whether this change would be clinically significant. These data show that cirrhosis impairs colchicine clearance and demonstrates that the liver is a major route of colchicine elimination.

Adult↗

PubMed1986

Colchicine inhibits ionophore-induced formation of leukotriene B4 by human neutrophils: the role of microtubules.

Neutrophils which ingest particles (serum-treated zymosan, monosodium urate crystals) or are exposed to calcium ionophore A23187 generate leukotriene B4 (LTB4). Earlier work has shown that cells exposed to colchicine before exposure to monosodium urate crystals produce less LTB4; the formation of 5-HETE is unaffected. To determine whether inhibition by colchicine of LTB4 generation was stimulus-specific and was mediated by microtubule integrity, the effects of colchicine (10 microM, 60 min) on the release of lipoxygenase products from neutrophils exposed to ionophore A23187 (10 microM, 5 min) were examined. In the presence of exogenous arachidonic acid (100 microM, 15 min), colchicine decreased LTB4 to 48% +/- 11.7 of control and 5-HETE to 60.5% +/- 5.7 of control (mean +/- SEM); 15-HETE was also decreased to 61% +/- 10.3 of control. In the absence of exogenous arachidonate, LTB4 was decreased to 22.2% +/- 11.7 of control and 5-HETE to 13% +/- 4.8 of control. Lumicolchicine did not significantly affect formation of 5-HETE or LTB4. However, vinblastine sulfate (20 microM, 60 min), another microtubule-disruptive agent, decreased the formation of both 5-lipoxygenase products. The effects of colchicine and vinblastine were not due to impairment of cell viability because the release of cytoplasmic lactic dehydrogenase was unaffected. Ultrastructural analysis of centriolar microtubules showed that decrements in microtubule numbers of colchicine- and vinblastine-treated cells paralleled decrements in 5-lipoxygenase products. These pharmacologic manipulations suggested that functional microtubules might be required for optimal lipoxygenase activity. Consequently, we prepared neutrophil-derived cytoplasts, devoid of an intact microtubule system. No significant decreases in the 5- or 15-lipoxygenase products were found when cytoplasts were exposed to colchicine in the presence of exogenous arachidonate and A23187. The data show that colchicine inhibits the formation of lipoxygenase products from neutrophils stimulated with A23187, most likely via its effect on microtubules, the integrity of which appears necessary for full expression of 5- and 15-lipoxygenases.

Adult↗

PubMed1987

Effect of colchicine on in vivo and in vitro ethanol metabolism in the rat.

Since colchicine has been used in the treatment of alcoholic cirrhosis of the liver, the effect of this drug on ethanol metabolism in the rat has been investigated. The acute intraperitoneal injection of colchicine (500 micrograms per kg body weight) did not significantly influence in vivo ethanol elimination rate nor the ethanol peak blood concentrations following an acute dose of ethanol (3 g per kg body weight). Cytoplasmic hepatic alcohol dehydrogenase activity was not changed by in vitro colchicine. However, an approximate 30% inhibition of hepatic microsomal ethanol oxidation was observed by colchicine at a concentration of 4 microM and more. In addition, when colchicine was given chronically in a daily dose of 50 micrograms per kg body weight for 3 weeks, again in vivo ethanol disappearance from the blood was not affected by the drug. These data indicate that neither acute nor chronic colchicine administration alters in vivo ethanol elimination. But the question is raised whether colchicine can decrease hepatic acetaldehyde concentration following a therapeutic dose in vivo by inhibiting the hepatic ethanol metabolizing enzyme system. This could be a possible explanation for the observation that alcoholics improve their liver function under colchicine therapy although they continue to drink.

Alcohol Dehydrogenase↗

PubMed1974

Inhibition of free fatty acid mobilization by colchicine.

Segments of epididymal adipose tissue from normal male rats were incubated with micromolar concentrations of colchicine for different periods of time up to 4 hr, and the mobilization of free fatty acids (FFA) was measured during a subsequent reincubation. Although pretreatment with colchicine did not alter basal unstimulated FFA release, mobilization of FFA in the presence of epinephrine or theophylline was reduced. However, neither lipolysis, as judged by glycerol production, nor cyclic AMP accumulation was impaired under the same conditions. To assess the possibility that colchicine might limit production of fatty acids by accelerating the entry and metabolism of glucose into adipocytes, the metabolism of glucose by adipose tissue was studied. Pretreatment with colchicine did not affect uptake of glucose nor its oxidation to CO(2), although colchicine-treated tissues did have slightly more [(14)C]glucose incorporated into the glyceride moiety of triglyceride. When adipose tissues pretreated with colchicine were incubated in an albumin-free medium, no reduction in FFA production by colchicine was observed. Because no FFA release occurs in albumin-free media, this experiment suggests that colchicine-induced inhibition of FFA mobilization results from impaired extrusion of FFA from adipose cells.

Adipose Tissue↗

PubMed1979

Denervation-like supersensitivity in the rat vas deferens induced by local application of colchicine to the hypogastric plexus.

In an attempt to induce denervation-like supersensitivity in the smooth muscle of the vas deferens without depriving the tissue of its innervation, a small amount of colchicine was locally applied to the hypogastric plexus of the rat. Colchicine produced supersensitivity and a partial depletion of the tissue norepinephrine. These effects were dose-dependent. The supersensitivity produced by colchicine was qualitatively and quantitatively similar to that induced by denervation. Following application of 20 micrograms of colchicine, the supersensitivity was fully developed by the 4th day. The supersensitivity began to decline by the 6th day but was measurable even after 16 days. Functional neuromuscular transmission was maintained even on the 4th day after colchicine application, although it was significantly less than the control. The time course of the development of supersensitivity was dependent on the length of the adrenergic nerve between the colchicine-applied site and the effector cells. The results indicate that supersensitivity is independent of an irreversible degeneration of the adrenergic nerves. The possible mechanisms of action of colchicine are discussed in relation to the known effects of colchicine on axoplasmic transport.

Animals↗

PubMed1983

[Amplification of portions of the genome in the somatic cells of mammals resistant to colchicine. V. The induction of gene amplification in the cells of the Djungarian hamster and the mouse].

The influence of some agents on gene amplification in Djungarian hamster and mouse cells was studied. The tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA), the epidermal growth factor (EGF), insulin, and 5-bromodeoxyuridine (BUdR) increase the incidence of colchicine-resistance, connected with amplification of the genes, which probably encode the polypeptide p22. The highest frequency of gene amplification was observed after the pretreatment of cells with TPA, which enhanced the number of colchicine-resistant colonies 44-200-fold. Mitostatic agents colchicine and colcemid increased the number of methotrexate-resistant cells, 2.0-6.5 times. These cells usually arise as the result of amplification of dihydrofolate reductase genes. Dexamethasone and ethidium bromide did not change the portion of cells resistant to colchicine. Ethylmethane sulfonate (EMS) decreased the number of colchicine-resistant cells. The cells of two Djungarian hamster colchicine-resistant clones obtained after treatment with TPA did not differ from those of spontaneously derived colchicine-resistant clones. Both have similar survival patterns in the medium with different colchicine concentrations, unstable inheritance of the drug resistance, the additional chromosome 4 and small chromatin bodies-the structures containing the amplified genes. Possible mechanisms of the induction of gene amplification by the agents used are discussed.

Animals↗

PubMed1982

The influence of colchicine on the cytotoxic effect of hydroxyurea in the embryonic spinal cord of the mouse.

The development of necroses and the course of the mitotic index in the embryonic spinal cord of 10-day-old mouse embryos (NMRI) were investigated between 1.5 h and 4 h after either an intraperitoneal application of 500 mg/kg hydroxyurea (HU) or 1 mg/kg colchicine or a simultaneous application of both substances. One h and 30 min after colchicine application, the mitotic index of the neuroepithelial cells had decreased (5.22%; control 7.7%). Subsequently, the mitotic index increased, reaching a maximum of 10.35% 2 h and 30 min after colchicine application. Between 1 h and 30 min and 4 h after HU application, the mitotic index decreased from 4.6% to 0.61% (control 7.7%). First necroses of neuroepithelial cells were observed 1 h and 50 min after HU application. 4 h after HU treatment, 34.38% of the neuroepithelial cells were necrotic. After simultaneous application of HU and colchicine, the decrease of the mitotic index was similar to the decrease after HU application alone. No necroses were observed in the embryonic spinal cord during a 4 h period after simultaneous application of HU and colchicine. After colchicine, as well as after simultaneous HU and colchicine application, the shape of the nuclei of the neuroepithelial cells changed from oval to round and the chromatin was condensed. Mechanisms for the inhibition of the cytotoxic but not the cytokinetic effects of HU by colchicine are discussed.

Animals↗

PubMed1980

Inhibition of H+ secretion in the turtle bladder by colchicine and vinblastine.

In order to investigate a possible role of the microtubules in urinary acidification we measured H+ secretion by the turtle bladder in vitro before and after addition of either colchicine or vinblastine to the serosal phase. Both colchicine and vinblastine inhibited H+ secretion in a dose-dependent fashion; in the control hemibladders H+ secretion remained unchanged. The half-maximal inhibition of H+ secretion occurred at 5.2 x 10(-5) M for colchicine and 7.2 x 10(-6)M for vinblastine. The inhibitory effect of colchicine and vinblastine on H+ secretion was maximal at 10(-4)M and 5 x 10(-4)M, respectively. At these concentrations these compounds failed to alter SCC and resistance. The inhibition of H+ secretion by colchicine or vinblastine increased with time of exposure to the drugs. The effect of colchicine or vinblastine on H+ secretion was not reversible with removal of the drug or with addition of 5% CO2 in the serosal phase. Lumicolchicine, an isomer of colchicine devoid of capacity to interact with microtubules, failed to alter the rate of H+ secretion, suggesting that the observed effect of colchicine on H+ secretion was the result of disruption of microtubule function and not the consequence of nonspecific effect of the drug. These data provide evidence for a role of microtubules in urinary acidification by the turtle bladder in vitro, but an effect of these drugs on membrane-bound tubulin cannot be excluded.

Animals↗

PubMed1980

The effects of calcitonin and colchicine on the cellular response to diphosphonate.

The mechanism by which diphosphonates inhibit bone resorption remains speculative; however, the osteoclast appears to be selectively affected by the drug. This study examined the effects off diphosphonate on osteoclasis in bones treated concomitantly with agents which reduce the osteoclast ruffled border, calcitonin and colchicine. Dichloromethylene diphosphonate, calcitonin, and colchicine inhibited parathyroid-hormone-stimulated bone resorption, as indicated by a significantly reduced release of 45Ca from prelabelled long bones. Quantitative and qualitative histological analyses of osteoclasts indicated differences among effects resulting from agents. Only bones treated with diphosphonate demonstrated a majority of osteoclasts with degenerative appearance; colchicine-treated bones exhibited many spherulated cells with cytoplasmic blebs. The number of normal osteoclasts in calcitonin-treated bones was the same as in controls and decreased with diphosphonate and colchicine treatment. All inhibitory agents reduced the number of nuclei per osteoclast; furthermore, colchicine effected an additional significant reduction, as compared with diphosphonate and calcitonin. The number and frequency of abnormal osteoclasts was increased by diphosphonate, but unaffected by colchicine and calcitonin. The addition of calcitonin, but not colchicine, to diphosphonate-treated bones decreased the incidence of abnormal osteoclasts. Although both calcitonin and colchicine are known to reduce the osteoclast ruffled border, this study has shown differences between the morphological effects of the 2 agents which presumably reflect differences in their mode of action and their interaction with diphosphonate.

Animals↗

PubMed1980

[Mouse cell accumulation of Colcemid and colchicine in tissue culture].

Kinetics of the uptake of 3H-colchicine and 3H-colcemid by mouse transformed L cells has been studied. The amounts of colchicine and of colcemid, accumulated by cells during a long-term incubation appeared to be equal; however, the initial uptake rates being higher for colcemid. The rates of the efflux of 3H-colchicine and 3H-colcemid were also different. After a 3 hours incubation of cells in antitubulin-free medium, the cells retain as much as 70% of colchicine, and only 10% of colcemid. It is known that colchicine does not bind tubulin at 0 degrees C; a colchicine analog lumicolchicine does not bind tubulin at any temperature. We have shown that the rate of 3H-lumicolchicine efflux at 37 degrees C is very rapid. The same was true for colchicine, if the incubation with the drug was performed at 0 degrees. We suggest that the difference in the rates of influx and efflux between colchicine and colcemid may be due to differences in their capacities of binding tubulin and dissociating from it.

Animals↗

PubMedDate not supplied

[Colchicine in chronic liver disease of alcoholic etiology. Double-blind, randomized study of its effects on blood levels of plasma proteins and clinical course in patients].

UNLABELLED: Patients with alcoholic chronic liver disease when treated with colchicine during a 12 month-period improved significantly the plasmatic levels of albumin and prothrombin when compared with a similar group of patients who took placebo. No differences in the mortality rate and in number of patients admitted at the hospital could be detected among those groups during this period. PURPOSE: To evaluate the clinical outcome and the plasmatic levels of albumin, pre-albumin, prothrombin and transferrin in patients presenting alcoholic chronic liver disease taking colchicine or placebo, during a 12-month period. METHODS: In a double-blind, randomized, controlled trial, 41 patients with alcoholic chronic liver disease were assigned to either placebo (20 patients) or a colchicine (21 patients) treatment group, assessing their clinical course (mortality rate and hospital admission) and plasmatic protein levels during a 12-month period. Albumin, pre-albumin and transferrin plasmatic levels were assessed through a immunodiffusion radial method and prothrombin time and activity was assessed by a one stage Quick modified method. RESULTS: At the end of the trial, only 7.3% of the patients were lost during follow-up. No statistical differences could be found in mortality and number of patients admitted at the hospital among placebo and colchicine groups. Comparatively to the placebo group, a significant increase in the mean of percentage variation was found in patients of the colchicine group for serum albumin levels (17.9% colchicine x 3.6% placebo, p < 0.05) and for prothrombin activity (19.2% colchicine x 2.1% placebo, p < 0.05). A similar pattern of response was found in pre-albumin serum levels, but such differences were not statistically different. No differences were found in serum transferrin levels among both groups. CONCLUSION: These results suggest that colchicine intake has a positive effect on plasmatic protein levels in patients with alcoholic chronic liver disease.

Adult↗

PubMed1997

Role of P-170 glycoprotein in colchicine brain uptake.

To study the role of P-glycoprotein (P-gp) in the delivery of colchicine from blood to brain, the pharmacokinetics of colchicine in plasma and brain was studied in the rat by an in vivo method and by the in situ brain perfusion technique. Colchicine was administered intravenously at three doses (1, 2.5, and 5 mg/kg) with or without an inhibitor of P-gp, verapamil (0.5 mg/kg i.v.); blood and brain samples were taken at t = 1, 2, and 3 hr. Areas under the colchicine curve at doses from 2.5 to 5 mg/kg were proportional to dose for plasma but not for brain. At a colchicine dose of 5 mg/kg, verapamil co-treated rats showed a 1.65-fold enhancement of the colchicine concentration in plasma but a 4.5-fold enhancement in brain. During short experimental times (in situ brain perfusion technique), a comparable enhancement was found (4.26-fold): mean distribution volumes of colchicine were enhanced from 0.23 +/- 0.17 to 0.98 +/- 0.19 microl/g for the eight gray areas, and no effect was observed in the choroid plexus, which do not express P-gp. These results clearly show that P-gp, present at the luminal surface of the capillary endothelial cells, is responsible for the weak penetration of colchicine into the brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Lack of therapeutic effect of colchicine on murine toxoplasmosis.

In a previous report, we showed that addition of colchicine to cultures of glial cells infected with Toxoplasma gondii decreased the number of parasites by up to 80%. To provide support for potential therapeutic use of colchicine in toxoplasmosis, a murine model of T. gondii infection was used. Mice infected with pure RH T. gondii tachyzoites (from 2,233 to 25,000 parasites) were treated daily with either pyrimethamine (80 or 51 mg/kg), colchicine (10 mg/kg), pyrimethamine-colchicine, or vehicle (controls). Survival rates were lower in animals treated with colchicine (from 40% to 27%) and pyrimethamine-colchicine (from 73% to 41%) than in animals treated with pyrimethamine alone (from 100% to 73%). There was no extension of mean survival time in animals treated with colchicine compared to controls. These results demonstrate that colchicine does not improve the course of acute toxoplasmosis in mice, and it is detrimental rather than beneficial at the regimen tested.

Administration, Oral↗