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PubMed1994

Renal secretion of vinblastine, vincristine and colchicine in vivo.

The MDR1 gene product, P-glycoprotein, has been localized to the apical surface of the renal proximal tubule, but its functional role in the kidney is unknown. We studied renal luminal and antiluminal uptake of three known substrates of P-glycoprotein: vinblastine, vincristine and colchicine, by using the single pass multiple indicator dilution method under control conditions and in the presence of increasing concentrations of cyclosporin A, a potent inhibitor of P-glycoprotein. A bolus of [125I]albumin (plasma reference), L-[14C]glucose (extracellular and glomerular reference) and tracer 3H-substrate was injected into the left renal artery of anesthetized dogs and timed serial samples were collected from the left renal vein and left and right ureters. In a single pass, approximately 38, 13 and 8% of [3H]vinblastine, [3H] vincristine and [3H]colchicine, respectively, was extracted from the postglomerular circulation. Drug binding to plasma proteins was determined to be 81% for [3H]vinblastine, 71% for [3H] vincristine and 23% for [3H]colchicine. Despite the high degree of drug protein binding, the urine recoveries of [3H]vinblastine, [3H]vincristine and [3H]colchicine relative to L-[14C]glucose were 0.75 +/- 0.06, 0.69 +/- 0.06 and 0.94 +/- 0.02, confirming net secretion of each of these substrates. Infusion of cyclosporin A (0.1-5 microM) significantly decreased the urine recovery of [3H] vinblastine and [3H]vincristine relative to L-[14C]glucose in a dose-dependent manner. The renal excretion of [3H]colchicine was not affected by cyclosporin A at the concentrations tested (1-2 microM). The evidence suggests that net secretion of [3H]vinblastine and [3H]vincristine occurs across the luminal membrane of the renal cell.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Binding of colchicine and thiocolchicoside to human serum proteins and blood cells.

The binding of 3H-colchicine and its derivative 3H-thiocolchicoside to human serum, purified human proteins and blood cells was studied by equilibrium dialysis and centrifugation. Binding of colchicine and thiocolchicoside to human serum was 38.9 C +/- 4.7 and 12.8 C +/- 5.3%, respectively, essentially to albumin. Protein binding was not dependent on the concentration of either drug between 10(-10) and 10(-5)M. The binding of colchicine and thiocolchicoside to isolated erythrocytes (55 C +/- 5.6 and 16.5 C +/- 2.1%, respectively) decreased markedly in the presence of human serum proteins, i.e. in whole blood (38.7 C +/- 3.1 and 3.4 C +/- 0.8%). Binding of colchicine and thiocolchicoside to other blood cells was very low C < 3%). These binding properties in the blood compartment do not predispose colchicine and thiocolchicoside to be pharmacokinetically sensitive to binding displacement by drug interactions.

Blood Platelets↗
PubMed1994

Colchicine disposition in patients with familial Mediterranean fever with renal impairment.

OBJECTIVE: To assess the pharmacokinetics of serum colchicine in patients with familial Mediterranean fever (FMF) with renal impairment. METHODS: Using a specific radioimmunoassay we determined serum colchicine concentration at various time points following oral administration of a single dose of the drug. RESULTS: Patients with renal insufficiency had a mean +/- SD apparent total colchicine clearance of 0.168 +/- 0.063 l/h/kg, apparent volume of distribution of 4.56 +/- 1.64 l/kg and elimination half-life (t1/2) of 18.8 +/- 1.2 h. Patients with FMF with normal kidney function had a mean clearance of 0.726 +/- 0.110 l/h/kg, volume of distribution of 4.87 +/- 2.05 l/kg and terminal t1/2 of 4.4 +/- 1.0 h. CONCLUSION: The kidneys have an important role in the clearance of colchicine. Caution should be exercised in the use of colchicine in patients with renal insufficiency.

Administration, Oral↗
PubMed1993

Colchicine is selectively neurotoxic to dentate granule cells in organotypic cultures of rat hippocampus.

Selective damage to dentate granule cells of the rat hippocampus was produced in organotypic hippocampal cultures by the addition of colchicine. Neuronal toxicity was assessed by quantifying the intensity of propidium iodide fluorescent staining of dying cells. Exposure to 1 microM and 10 microM doses of colchicine for 1 hour caused highly specific dentate granule cell toxicity after 24 hours whereas 100 microM was also slightly toxic to pyramidal cells. Forty eight hours following colchicine exposure additional damage to dentate granule cells and also slight damage to pyramidal cells was seen at all doses. This study demonstrates that dentate granule cells in organotypic hippocampal cultures are selectively vulnerable to colchicine and that colchicine can be used as a tool to selectively destroy the dentate in this preparation.

Animals↗
PubMed1977

[Effect of colchicine on the morphogenesis and ultrastruct of Acetabularia mediterranea].

The effect of colchicine on morphogenesis of the regenerating nuclear fragments of Acetabularia mediterranea has been studied. Colchicine was shown to inhibit the formation of caps. The algae are most sensitive to colchicine at the early stages of regeneration. The breakdown of microtubules in the perinuclear cytoplasm of regenerating algae under the effect of colchicine was found under the electron microscopy. The breakdown of microtubules in this zone appears not to disturb the transport of morphogenetical substances in the apical cell part. Colchicine inhibits the morphogenesis, apparently, at the expense of protein inactivation in the zone of growth.

Acetabularia↗
PubMed1997

Comparative effects of colchicine and silymarin on CCl4-chronic liver damage in rats.

The comparative effects of colchicine (10 micrograms day-1, p.o.) and silymarin (50 mg kg-1, p.o.) each given for 5 days a week on the chronic carbon tetrachloride (CCl4) liver damage were studied. Treatment with CCl4 resulted in a marked reduction of Na+, K+, and Ca2(+)-ATPases in plasma liver membranes as compared to vehicles or either silymarin or colchicine alone. Collagen content in livers of animals treated with CCl4 was increased about four-fold as compared to controls and histological examination of liver samples showed that collagen increase distorted the normal liver architecture. Colchicine or silymarin treatment completely prevented all the changes observed in CCl4-cirrhotic rats (namely, lipid peroxidation, Na+, K+ and Ca(2+)-ATPases), except for liver collagen content which was reduced only 55% as compared with CCl4-treated rats and for alkaline phosphatase and glutamic pyruvic transaminase which still remained above controls. In the CCl4 + silymarin group, the loss of glycogen content was completely prevented. However, when rats were treated with CCl4 + colchicine, liver glycogen content could not be restored. The hepatoprotective effects of colchicine or silymarin were very similar in regard to the prevention of chronic liver damage.

Animals↗
PubMed1976

The in vivo effect of colchicine on the addition of galactose and sialic acid to rat hepatic serum glycoproteins.

Colchicine inhibits the secretion of plasma protein by rat hepatocytes and causes their intracellular accumulation in Golgi-derived secretory vesicles. This study examines whether colchicine affects secretion before or after galactose and sialic acid have been added to the secretory glycoproteins. D-[G-3H] Galactose was injected into rats and was found to be incorporated into serum glycoproteins contained within Golgi-derived secretory vesicles. The administration of colchicine (25 mumol/100 g, body weight), immediately before the injection of D-[G-3H] galactose, caused an increase in radioactivity of the serum glycoproteins in these cell fractions. D-[G-3H] Glucosamine was incorporated into serum glycoproteins contained within the rough and smooth endoplasmic reticulum and the Golgi cell fractions; however, its incorporation into the sialic acid moieties of these proteins only occurred in Golgi-derived cell fractions. Colchicine administration resulted in an increased incorporation of D-[G-3H] glucosamine into the sialic acid residues of serum glycoproteins contained within the Golgi cell fractions. These data indicate that colchicine inhibits secretion of serum proteins by rat liver after the addition of galactose and sialic acid to the secretory proteins has taken place.

Animals↗
PubMed1976

Colchicine-sensitive structures and lymphocyte activation.

The possible modulatory role of microtubules or closely related colchicine-sensitive structures in the response of human lymphocytes to mitogenic lectins was investigated. Colchicine (0.1 to 10 muM) AND VINBLASTINE (0.1 TO 10 MUM) inhibited early [14C]-aminoisobutyric acid and late [3H]-thymidine uptake in phytohemagglutinin-and concanavalin A-stimulated human lymphocytes but failed to alter 45Ca uptake. Lumicolchicine, an inactive congener of colchicine, was ineffective in all three systems. Both microtubular agents accentuated and prolonged the early cyclic AMP response to lectin. Little or no alteration in cyclic AMP levels was seen with colchicine or vinblastine alone or in combination with PGE (10MUM) or epinephrine (1muM) suggesting that the effect on cyclic AMP metabolism is largely selective for lectin stimulation. Neither microtunular agent altered 125I-concanacalin A binding. Since the inhibition of DNA synthesis was throughout the culture period and early aminoisobutyric acid uptake is affected, it appears that these agents are acting on an early event, or events, in the activation sequence. Although the mechanism of the inhibition is not known, the effect of colchicine and vinblastine in prolonging the cyclic AMP response to lectin may be involved. Alternatively, alterations in microtubules assembly may exert effects on membrane architecture interfering with propagation of the stimulus from the membrane to the cell interior.

Aminoisobutyric Acids↗
PubMed1998

Treatment with colchicine and survival of patients with ascitic cirrhosis: a double-blind randomized trial.

BACKGROUND: In order to assess the role of colchicine in the survival of cirrhotic patients, 52 patients were studied. METHODS: The patients were divided into two groups, randomized according to age. There were no significant differences in age, sex, etiologic factors, or biological data. In addition to conventional therapy with diuretics, the first group was treated with colchicine of 1 milligram daily for 5 days a week, and the second group with a placebo. RESULTS: Under the action of colchicine, the diuretics were discontinued because the ascites disappeared in 37.93% of the colchicine group, vs 4.35% of the placebo group (p < 0.01). At time of discharge from the clinic, ascitic fluid disappeared respectively in 72.41% and 26.09% of cases (p < 0.001), whereas the recurrence in the follow-up period was 47.62% vs 83.33% (p < 0.1). CONCLUSIONS: Using Kaplan Meier survival curves, and comparing both groups with Logrank test during a period of 11 years it was found that survival of the colchicine group was 3 times greater than that of the placebo group (p < 0.001).

Adult↗
PubMed1995

Misoprostol Stimulates cAMP Generation in Human Leukocytes: Synergy with Colchicine Suggests a New Potential for Established Drugs.

In isolated leukocytes, elevation of cAMP can inhibit various proinflammatory and immune functions. The prostaglandins E (PGEs) are known to stimulate leukocyte cAMP production, and for years they have been viewed as potential immunosuppressive and/or anti-inflammatory agents. However, their clinical use is severely limited by extreme metabolic instability and by poor oral absorption, which necessitates administration by infusion or injection. Misoprostol is a synthetic analog of PGE(1) that is relatively stable and orally absorbable. We examined the effects of misoprostol on cAMP production in leukocytes, in view of the possibility that it mimics PGE(1) and, thus, might represent a clinically useful immunosuppresive or anti-inflammatory drug. Our results indicate the following: (1) Misoprostol increases leukocyte cAMP production in a dose-dependent manner (similar20 nM to >100 &mgr;M) and acts by stimulating adenylate cyclase. (2) Its potency and maximal effect are somewhat less than those of PGE(1) (3) cAMP generation in response to either misoprostol or PGE(1) is transient (in the presence of isobutylmethylxanthine to inhibit endogenous phosphodiesterases). (4) Misoprostol's stimulation of adenylate cyclase is synergistically increased by pretreatment of cells with colchicine, a microtubule-disrupting agent that is currently used for prophylaxis and treatment of gout. (5) Colchicine acts by increasing the initial rate of cAMP production and not by prolonging the response to misoprostol. (6) A clinically relevant dose of colchicine (0.25 &mgr;M) is effective given sufficient pretreatment time. (7) Whereas a clinically relevant dose of misoprostol (3 nM) is ineffective alone, preexposure of cells to colchicine enables such a dose to stimulate cAMP generation significantly. The combination of misoprostol with colchicine might eventually prove useful in the therapy of immune or inflammatory disease.

Journal Article↗
PubMed2005

Comparison of colchicine, dapsone, triamcinolone, and diphenhydramine therapy for the treatment of brown recluse spider envenomation: a double-blind, controlled study in a rabbit model.

OBJECTIVE: To compare the efficacy of dapsone, diphenhydramine, colchicine, and intralesional triamcinolone in the treatment of brown spider bites. We used a purified venom that reproducibly produces a large eschar. To mimic real-life circumstances, all agents were administered following a 2-hour delay after envenomation. The animals were evaluated for the presence of coagulopathy to determine if the incidence of systemic findings correlated with the type of treatment. DESIGN AND SETTING: In a research laboratory, 60 New Zealand white rabbits each received an intradermal injection of 20 microg of purified Loxosceles reclusa venom. The rabbits were divided into 5 groups of 12; a control group and 4 groups treated with a drug (either colchicine, triamcinolone, diphenhydramine, or dapsone). Measured end points included maximum eschar size as well as histologic grading of depth, inflammation, and thrombosis. INTERVENTIONS: Treatment with colchicine, triamcinolone, diphenhydramine, or dapsone. MAIN OUTCOME MEASURES: Maximum eschar size as well as histologic grading of depth, inflammation, and thrombosis. RESULTS: There was no significant difference with respect to eschar size (1-way analysis of variance, P = .003). There was no significant difference between any treatment with respect to presence or absence of ulcer, necrosis, large vessel vasculitis, or small vessel vasculitis. The only outcome of significance was that triamcinolone offered protection from thrombosis (chi2 likelihood ratio, P = .04). We also noted evidence of coagulopathy in all of the envenomated animals. The rabbits had grossly elevated activated partial thromboplastin time results, which were corrected with 1:1 mixing with normal rabbit plasma, suggesting an acquired factor deficiency. We did not detect an individual factor deficiency or a lupus anticoagulant. CONCLUSIONS: In a rabbit model, none of the agents tested (dapsone, diphenhydramine, colchicine, and intralesional triamcinolone) had an effect on eschar size. Triamcinolone appeared to offer some protection against histologic evidence of thrombosis, but this protection did not translate into a difference in clinical outcome. All animals developed evidence of coagulopathy, regardless of treatment. The coagulopathy could be corrected by fresh rabbit plasma, suggesting an acquired factor deficiency.

Animals↗
PubMed1986

Oral colchicine for the treatment of experimental traction retinal detachment.

In proliferative vitreoretinopathy and trauma, long-term reattachment of the retina is often prevented by the formation of contractile cellular membranes on the retinal surface and within the vitreous cavity. Colchicine, a well-documented inhibitor of microtubule assembly, is a potent inhibitor of retinal pigment epithelium cell, astrocyte, and fibroblast proliferation and migration. To study the therapeutic value of orally administered colchicine, we used an experimental animal model in which intravitreally injected platelet-derived growth factor and fibronectin produced traction retinal detachments in rabbits. With oral administration of colchicine, we were able to decrease the incidence and severity of traction retinal detachment from 74% in controls (20 of 27 eyes) to 29.6% in the treated animals (eight of 27 eyes) at five weeks (P less than .0009). These results, and the apparent lack of retinal and systemic toxicity, suggest that oral therapy with colchicine may prove to be of value in the treatment of human disease.

Administration, Oral↗
PubMed1988

Treatment of severe recurrent aphthous stomatitis with colchicine.

Recurrent aphthous stomatitis (RAS) is characterized by necrotizing ulcers of the oral mucosa that persist, remit, and recur for variable periods of time. Despite the benign nature of the disease, persistent pain and ulceration may disable patients from performing their daily activities. We describe three patients with long-standing active RAS treated with oral colchicine. All patients experienced a marked decrease in symptoms and a remission of the disease. Recurrences, however, occurred within three days of discontinuation of the therapy. In one patient, colchicine therapy was discontinued because of persistent diarrhea. In another, a second remission was more difficult to achieve on the same regimen. The literature on the subject is reviewed, and the beneficial effects of colchicine therapy are discussed in relation to the immunopathogenesis of this disease. We conclude that colchicine therapy should be considered as an alternative in the treatment of the major or persistent form of RAS.

Adult↗
PubMed1999

Complexation and ionophoric properties of taxol and colchicine: complex formation and transport of sodium, potassium, magnesium and calcium ions across a liquid membrane.

We report the activities of taxol (an anticancer drug) and colchicine, which are inhibitors of microtubule organization, on the complexation and transport of Na+, K+, Mg2+ and Ca2+ ions across a liquid membrane, using a spectrophotometric procedure. Taxol, a diterpenoid compound, that has been demonstrated to possess a potent antitumour activity, is shown to extract Na+, K+, Mg2+ and Ca2+ ions from the aqueous solution to the organic phase with preference for Ca2+ ions. A kinetic study of the transport and complexation of Na+, K+, Mg2+ and Ca2+ ions through a liquid membrane revealed that the K+ ion is more rapidly transported and the Ca2+ ion is more rapidly complexed than other ions. However, colchicine, another alkaloid compound, extracted and transported only the divalent ions tested, Mg2+ and Ca2+. In both complexation and transport, the flux of the ions increases with the concentration of taxol or colchicine. Complexation and ionophoric properties of taxol and colchicine sheds new lights on therapeutic properties of these drugs. The treatment of disease states by the administration of these drugs to alter membrane permeability will prove to be a valuable therapeutic concept.

Antineoplastic Agents, Phytogenic↗
PubMed1984

Influence of colchicine and vinblastine on the intracellular migration of secretory and membrane glycoproteins: I. Inhibition of glycoprotein migration in various rat cell types as shown by light microscope radioautography after injection of 3H-fucose.

Previous studies have shown that colchicine and vinblastine inhibit secretion in many cell types by interrupting the normal intracellular migration of secretory products. In the present work, radioautography has been used to study the effects of these drugs on migration of membrane and secretory glycoproteins in a variety of cell types. Young (40 gm) rats were given a single intravenous injection of colchicine (4.0 mg) or vinblastine (2.0 mg). At 10 min after colchicine and 30 min after vinblastine administration, the rats were injected with 3H-fucose. Control rats received 3H-fucose only. All rats were sacrificed 90 min after 3H-fucose injection and their tissues processed for light microscope radioautography. Examination of secretory cell types such as ameloblasts and thyroid follicular cells in control animals revealed reactions of approximately equal intensity over the Golgi region and over extracellular secretion products, while in drug-treated rats most of the reaction was confined to the Golgi region. In a variety of other cell types, including endocrine cells (e.g., hepatocytes) and cells generally considered as nonsecretory (e.g., intestinal columnar cells), reaction in control animals occurred both over the Golgi region and over various portions of the cell surface. In drug-treated animals, a strong Golgi reaction was present, but reaction over the cell surface was weak or absent. These results indicate that in many cell types, colchicine and vinblastine inhibit migration out of the Golgi region not only of secretory glycoproteins, but also of membrane glycoproteins destined for the plasma membrane.

Animals↗
PubMed1984

Influence of colchicine and vinblastine on the intracellular migration of secretory and membrane glycoproteins: II. Inhibition of secretion of thyroglobulin in rat thyroid follicular cells as visualized by radioautography after 3H-fucose injection.

Young (40 gm) rats were given a single intravenous injection of colchicine (4.0 mg) or vinblastine (2.0 mg). At 10 min after colchicine and 30 min after vinblastine administration, the rats were injected with 3H-fucose. Control rats received 3H-fucose only. All rats were sacrificed 90 min after 3H-fucose injection and their tissues processed for radioautography. In thyroid follicular cells of control animals, at this time interval, 57% of the total label was associated with colloid and secretory vesicles in the apical cytoplasm while 27% was localized in the Golgi apparatus and neighboring vesicles. In experimental animals, the proportion of label in colloid and apical vesicles was reduced by more than 69% after colchicine and more than 83% after vinblastine treatment. The proportion of label in the Golgi region, on the other hand, increased by more than 125% after colchicine and more than 179% after vinblastine treatment. Within the Golgi region, the great majority of the label was associated with secretory vesicles which accumulated adjacent to the trans face of the Golgi stacks. It is concluded that the drugs do not interfere with passage of newly synthesized thyroglobulin from the Golgi saccules to nearby secretory vesicles, but do inhibit intracellular migration of these vesicles to the cell apex. In most cells the number of vesicles in the apical cytoplasm diminished, but this was not always the case, suggesting that exocytosis may also be partially inhibited. The loss of microtubules in drug-treated cells suggests that the microtubules may be necessary for intracellular transport of thyroglobulin.

Animals↗
PubMed1976

Response of tanycytes of rat median eminence to intraventricular administration of colchicine and vinblastine.

The effects of colchicine and vinblastine on tanycytes of the rat median eminence have been studied using the electron microscope. Colchicine and vinblastine were administered by intraventricular cannulation into the third ventricle and demonstrated distinct morphological effects on tanycyte microtubules. Highest drug doses administered were 50.0 mug in 5.0 mul of saline initially, followed by an additional 50.0 mug of these agents infused in a volume of 13.0 mul saline over an hour. Colchicine treatment resulted in the formation of large crystalloids within tanycytes, coincident with the disappearance of microtubules, all along the ventricular surface. Nonetheless the tanycytes appeared able to maintain a continuous, tight lining, as in controls, although some crystalloids were observed beneath the ventricular surface, either within tanycyte processes or within neuronal processes. Vinblastine treatment also resulted in the formation of identical crystalloids but at highest doses thoroughly destroyed the tanycyte lining of the median eminence and exposed cellular elements below the surface to the drug. Portal capillaries approaching the ventricular surface were generally free of any signs of drug response to either colchicine or vinblastine.

Animals↗
PubMed1991

Long-term colchicine treatment in children with familial Mediterranean fever.

Three hundred fifty children (younger than age 16) who had familial Mediterranean fever (FMF) were given continuous prophylactic treatment with colchicine (1-2 mg/day) for 6-13 years. Complete remission of febrile attacks was achieved in 64% of the patients, and partial remission in 31%. Protracted attacks of arthritis virtually disappeared. None of the children developed amyloidosis while on the colchicine regimen. Side effects of colchicine were insignificant, and did not prompt permanent discontinuation of treatment in any of the children. Their growth, development, and subsequent fertility were normal. The efficacy of long-term colchicine treatment of children with FMF makes early diagnosis life saving.

Adolescent↗