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PubMed1998

Colchicine in chronic hepatitis B: a pilot study.

RATIONALE: Because of its antifibrotic and anti-inflammatory effects, colchicine has been proposed as a treatment for liver disease. Early in vitro studies have demonstrated that colchicine blocks mitosis in the metaphase and inhibits DNA synthesis. AIM: A pilot study of hepatitis B virus (HBV)-related/HBV-DNA+ve chronic liver disease. PATIENTS: Nine biopsy-proven chronic hepatitis patients (three with cirrhosis) entered the study. Two of them were HBeAg+ve and seven were antiHBe+. All patients were HBV-DNA+ve/antiHBc IgM+ve (index values of anti-HBc IgM ranged from 0.370 to 1.200). All of them had a major contraindication to interferon therapy or refused antiviral treatment. The known persistence of positive HBsAg ranged from 2 to 21 years. METHODS: After informed consent, the patients received 1 mg colchicine a day orally for 5 days-a-week over 6 months. Testing for liver enzymes and viral markers was performed at the baseline and after 3 and 6 months. RESULTS: None of the patients experienced side-effects during the treatment. The two HBeAg+ve patients seroconverted to anti-HBe with a normalization of AST/ALT during therapy. Among the seven antiHBe+ve patients, four had a complete normalization of transaminases (one patient cleared the HBsAg with seroconversion to anti-HBs). Six of the nine patients were HBV-DNA-ve at the end of therapy and were still negative after 12 months of follow-up. CONCLUSION: These preliminary results suggest that colchicine might have an antiviral activity in HBV-DNA+ve chronic liver disease, and it could be regarded as an alternative therapy to interferon.

Administration, Oral↗
PubMed2001

Ten-year combination treatment with colchicine and ursodeoxycholic acid for primary biliary cirrhosis: a double-blind, placebo-controlled trial on symptomatic patients.

BACKGROUND: Combined medical treatment may provide further benefit to primary biliary cirrhosis (PBC) patients administered ursodeoxycholic acid (UDCA). AIM: To evaluate the long-term effects of colchicine and UDCA in symptomatic PBC patients. PATIENTS/METHODS: We extended up to 10 years the double-blind treatment of 44 symptomatic PBC patients originally included in a 3-year multicentre study comparing UDCA and colchicine (U + C) versus UDCA and placebo (U + P). Outcome measures were death or liver transplantation; incidence of clinically relevant events; clinical and quantitative variables retaining prognostic information. RESULTS: Mean follow-up was 7 +/- 3 years. One patient was lost, three withdrew because of jaundice (U + P); two patients stopped colchicine but remained on UDCA. Eleven patients (two for liver-unrelated reasons, U + P) and six patients (U + C) died, three and two patients, respectively, were transplanted (incidence rate difference, five cases per 100 patient-years; 95% CI, -1 to 11). Hepatocellular carcinoma developed in one (U + P) and four (U + C) patients (difference, -2; CI, -5 to 1), portal hypertension complications in nine patients from each group (difference, 1; CI, -5 to 6). Trends of serum bilirubin, Mayo score, antipyrine clearance were similar among treatment groups. CONCLUSIONS: In cirrhotic PBC patients, colchicine does not offer additional benefits to UDCA. In this population, UDCA does not obviate disease progression.

Colchicine↗
PubMed1997

Colchicine as a novel therapeutic agent in chronic bullous dermatosis of childhood.

BACKGROUND: The treatment of chronic bullous dermatosis of childhood (CBDC) so far has been limited to the use of corticosteroids and the sulfa group of drugs, e.g. daspsone and sulfapyridine. Furthermore, the therapy of CBDC cases with associated G6 PD deficiency is restricted only to systemic steroids. Histopathologically CBDC is characterized by the presence of predominantly neutrophilic infiltration and because it has been proven to exert strong anti-inflammatory effects through the inhibition of neutrophils, colchicine was mandated for its use in CBDC. METHODS: To avoid the detrimental side-effects of the long-term use of steroids in children, an alternative anti-inflammatory drug like colchicine was considered. Patients with G6 PD deficiency and those who were not satisfactorily controlled with steroid therapy, and who in addition developed unacceptable side-effects like cushingoid faces and hypertrichiosis, were treated with the drug. RESULTS: Eight patients were given colchicine, five (62.5%) of which showed complete remission within 4-6 weeks of starting the therapy. The remaining three (37.5%) also responded but required adjuvant small doses of steroids to maintain the remissions. The drug was very well tolerated and no side-effects were observed. CONCLUSIONS: Colchicine is, therefore; found to be an effective treatment in CBDC and has enhanced our armamentarium of therapeutics for this condition, especially in children with G6 PD deficiency.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Lithium prevents colchicine-induced apoptosis in rat cerebellar granule neurons.

OBJECTIVES: Here we evaluated the neuroprotective effects of two well-known mood stabilizers, lithium and valproic acid (VPA), against colchicine neurotoxicity in cerebellar granule cells (CGNs). METHODS: The CGNs were differentiated for 7 days, pretreated with lithium or VPA for 24 h and after colchicine 1 microM was added. Cellular damage was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) method and apoptosis in CGNs was characterized by chromatin condensation and DNA fragmentation. RESULTS: Incubation with lithium (1-5 mM) attenuated this apoptosis markedly, in a dose-dependent way however, the addition of VPA (0.5-2 mM) did not protect CGNs. Colchicine-induced apoptosis is mediated through the activation of caspase-3. An increase in caspase-3 activity was detected within 18 h and was blocked in presence of lithium 5 mM. CONCLUSIONS: Our data indicate that lithium treatment is selectively neuroprotective; however, in our experimental conditions VPA did not protect CGNs from apoptosis induced by colchicine. Our results support the hypothesis that distinct pathways mediate the neuroprotective effects of lithium and VPA.

Animals↗
PubMed2003

Combined treatment with vitamin E and colchicine in the early stages of Peyronie's disease.

OBJECTIVE: To assess the effectiveness of the combination of colchicine and vitamin E (which has anti-fibrotic, anti-mitotic and anti-inflammatory effects) in modifying the early stages of Peyronie's disease, by evaluating pain relief, correction of deformities and plaque size. PATIENTS AND METHODS: In all, 45 patients were divided into two groups and treated from January 1998 to November 2001. Their mean (range) age was 53.4 (40-62) years, the time from onset of the disease < 6 months and they had penile deformity of < 30 degrees; no patient had erectile dysfunction. Twenty-two patients were given ibuprofen 400 mg/day for 6 months, whilst 23 received a combination of vitamin E 600 mg/day plus colchicine 1 mg every 12 h. Pain, plaque size and penile deformity were assessed at 6 months. RESULTS: There were no statistically significant differences between the groups at baseline in age, time from onset of the disease until the initial evaluation or plaque size. Although the proportion of patients reporting pain relief was higher amongst those receiving colchicine plus vitamin E (91% vs 68%) this was not significantly different, but differences in plaque size and penile curvature were significant. CONCLUSIONS: The use of colchicine plus vitamin E during the early stages of Peyronie's disease (time from onset < 6 months) in patients with penile curvature of < 30 degrees and no erectile dysfunction is an effective and well-tolerated way to stabilize the disease. A more extensive study is needed, comparing these results with other oral therapies.

Adult↗
PubMed1997

The use of methotrexate, colchicine, and other immunomodulatory drugs in the treatment of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an immunologically mediated disease in which activated T lymphocytes attack and destroy epithelial cells in the small intralobular bile ducts of genetically susceptible patients. This article reviews the results of treatment of PBC with immunomodulatory agents. Results with drugs such as glucocorticoids, azathioprine, and chlorambucil have been disappointing because of either limited efficacy (azathioprine), toxicity (chlorambucil), or both (glucocorticoids). Colchicine improved tests of liver function in three prospective studies and was associated with improved survival for up to 4 years. However, survival benefits were lost at 8 years. Colchicine appears to slow the rate of progression of PBC but not to stop it. Preliminary results suggest that colchicine may have synergistic effects if used together with ursodeoxycholic acid, particularly in patients who are only partially responsive to ursodeoxycholic acid. Results with cyclosporine have been disappointing because of limited efficacy and predictable toxicity. The modest improvement in tests of liver function and survival are counterbalanced by the development of hypertension in some and worsening renal function in most. There is little beneficial effect on symptoms or histology. Results with methotrexate are promising. There are improvements in symptoms and tests of liver function that are equal to those seen with ursodeoxycholic acid and significant improvement in liver histology. Some patients, particularly those with striking inflammation and granulomas in portal triads, appear to have achieved sustained remission while on methotrexate. The effects of methotrexate are additive to those of ursodeoxycholic acid in patients whose blood tests have responded only partially to ursodeoxycholic acid. The most effective treatment of PBC will most likely use a combination of drugs such as ursodeoxycholic acid, colchicine, and methotrexate.

Adjuvants, Immunologic↗
PubMed1980

[Colchicine sensitivity index: a means of distinguishing benign and malignant lymphocytic cutaneous infiltrates (author's transl)].

Lymphocytes in patients with chronic lymphatic leukaemia and other malignant lymphomas have an abnormally high sensitivity to colchicine in vitro. This can be expressed in a colchicine-sensitivity index and used diagnostically. Lymphocytes isolated from cutaneous infiltrates in mycosis fungoides, a cutaneous malignant T-cell lymphoma, had an increased colchicine-sensitivity index of 44 (P < 0.01). On the other hand, lymphocytes from cutaneous infiltrates of reactive inflammatory dermatitis cases had an index of 23. It would seem that the colchicine-sensitivity index is helpful in the diagnosis of selected cases of cutaneous malignant lymphomas.

Adult↗
PubMed2002

Topical colchicine selection of keratinocytes transduced with the multidrug resistance gene (MDR1) can sustain and enhance transgene expression in vivo.

For skin gene therapy, achieving prolonged high-level gene expression in a significant percentage of keratinocytes (KC) is difficult because we cannot selectively target KC stem cells. We now demonstrate that topical colchicine treatment can be used to select, in vivo, KC progenitor cells transduced with the multidrug resistance gene (MDR1). When human skin equivalents containing MDR1-transduced KC were grafted onto immunocompromised mice, topical colchicine treatments significantly increased (7-fold) the percentage of KC expressing MDR1, compared to vehicle-treated controls, for up to 24 wk. Topical colchicine treatment also significantly enhanced the amount of MDR1 protein expressed in individual KC. Furthermore, quantitative real-time PCR analysis of MDR1 transgene copy number demonstrates that topical colchicine treatment selects and enriches for KC progenitor cells in the skin that contain and express MDR1. For clinical skin gene therapy applications, this in vivo selection approach promises to enhance both the duration and expression level of a desired therapeutic gene in KC, by linking its expression to the MDR1 selectable marker gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1975

Membrane-microtubule interactions: concanavalin A capping induced redistribution of cytoplasmic microtubules and colchicine binding proteins.

The relationship between microtubules and concanavalin A surface receptors during concanavalin A capping in primary cultures of rabbit ovarian granulosa cells was examined by electron microscopic and fluorescence labeling techniques. Cells treated with concanavalin A and hemocyanin at 4 degree or 37 degree and then incubated at 37 degree for 1 hr formed large juxtanuclear caps that were observed with shadow cast replicas of the cell surface. Thin section analysis of capped cells revealed an abundance of microtubules immediately beneath the cap which were arranged approximately perpendicular to the plane of the membrane. The capping process was unaffected by the antimicrotubule agents colchicine or vinblastine. Further, vinblastine treatment of capped calls resulted in the formation of numerous paracrystals that were confined to the cytoplasm underlying the capped region of the membrane; uncapped cells displayed paracrystals that were randomly dispersed in the cytoplasm. Exposure of fixed cells to fluorescein thiocarbamyl colchicine, which localizes colchicine binding proteins, revealed an intensely fluorescent region that corresponded to the cap; this staining pattern was absent in uncapped cells. These findings indicate that concanavalin A mediated capping modifies the cytoplasmic disposition of microtubules and colchicine binding proteins. Further, it is suggested that the capped region of the plasma membrane is a preferred site of microtubule polymerization.

Animals↗
PubMed1976

Secretion of macrophage neutral proteinase is enhanced by colchicine.

We have studied the effect of colchicine and related compounds on secretion of enzymes by thioglycollated-elicited mouse peritoneal macrophages in culture. Colchicine stimulated secretion of inducible neutral proteinase activities of elastase (EC 3.4.21.11), collagenase (EC 3.4.24.3), gelatinase (pepsin B; EC 3.4.23.2), and azocaseinase 2- to 6-fold for a period of several days, but inhibited the production and release of lysozyme (mucopeptide N-acetylmuramoylhydrolase; EC 3.2.1.17), a noninducible macrophage secretory product. Parallel changes were observed in cell morphology and secretion after treatment with colchicine, Colcemid, and vinblastine, but not with lumicolchicine, and these effects could be gradually reversed by withdrawal of colchicine. Cytochalasin B also stimulated secretion of elastase 2- to 3-fold but did not influence release of lysozyme. These results demonstrate that tubulin-binding drugs may have opposite effects in macrophages than those usually reported for other experimental systems and also provide evidence for the nonparallel discharge of different macrophage secretion products.

Colchicine↗
PubMed1979

Competitive inhibition of colchicine binding to tubulin by microtubule-associated proteins.

Microtubule-associated proteins (MAPs) promote tubulin polymerization, whereas colchicine inhibits this process. In this paper, MAPs have been shown to inhibit colchicine binding to tubulin in a competitive manner. Attempts were made to identify which of the MAPs fraction(s) was responsible; both tau protein (a thermostable molecule with a molecular weight of approximately 70,000) and a high molecular weight fraction (HMW) were able to compete with colchicine. In contrast, Mg2+, which also induces microtubule assembly in vitro, had no effect on colchicine binding to tubulin.

Animals↗
PubMed1980

Colchicine inhibits epidermal growth factor degradation in 3T3 cells.

Colchicine (2 microM) did not affect the initial rate of association of 125I-labeled epidermal growth factor (125I-EGF) to Swiss 3T3 cells but continued incubation (up to 24 hr) led to an increase in cell-associated radioactivity. The effect is also produced by Colcemid, vinblastine, and podophyllotoxin but not by lumicolchicine. Disruption of microtubules with colchicine does not alter the rate of "down regulation" of EGF receptors, suggesting the binding and internalization of the factor proceed unchanged. However, colchicine markedly decreases the rate of appearance of acid-soluble radioactivity from cells either incubated continuously with 125I-EGF for 24 hr or exposed to the radioactive peptide for only 1 or 3 hr. The results indicate that colchicine decreases the rate of degradation of internalized 125I-EGF. Because antitubulin agents enhance the mitogenic effect of EGF our results suggest that peptide degradation can be dissociated from the long-term biological effect.

Ammonium Chloride↗
PubMed1986

B ring regulation of colchicine binding kinetics and fluorescence.

Several properties of the colchicine-tubulin interaction such as association rate, reversibility, and the promotion of drug fluorescence have been related to the B ring of colchicine. The B ring itself retards the binding rate, and substitution at C-7 leads to further binding rate decreases that appear to be related to both substituent bulk and the presence of a N-acyl group. Thus, the decreasing order of binding rates is 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone greater than deacetamidocolchicine greater than deacetylcolchicine greater than or equal to colcemid greater than colchicine greater than N-benzoyldeacetylcolchicine, etc. The apparent irreversibility of the binding seems more closely related to the presence of an N-acyl group rather than the bulk of the substituent at C-7. Substitution at C-7 also affects the tropolone fluorophore. Thus, amines (deacetylcholchicine, colcemid, or N-methylcolcemid) fluoresce poorly in the presence of tubulin, whereas substitution of the amino group with an acyl group enhances fluorescence. The presence of an N-acyl group at C-7 is essential for enhanced fluorescence. We conclude that, in addition to A- and the C-ring portion of the molecule, the B ring of colchicine is a third determinant recognized by the binding site on tubulin.

Animals↗
PubMed1995

Colchicine binding by the "isolated" beta-monomer of tubulin.

At mole ratios of lactoperoxidase to tubulin monomers of 3-4, bovine lactoperoxidase forms 1:1 adducts with both alpha- and beta-tubulin from rat brain, thereby separating the tubulin heterodimer into its monomers. This mixture binds colchicine normally, and we show here by direct photoaffinity labeling that the bulk of the [3H]colchicine becomes attached to beta-tubulin under these conditions. When the alpha-tubulin has been displaced by lactoperoxidase, the ratio of label in beta-tubulin to alpha-tubulin is increased. The amount of label in alpha-tubulin decreases with a corresponding appearance of label in lactoperoxidase. The rate of labeling of beta-tubulin remains slow. We conclude that alpha-tubulin is not necessary for colchicine binding and propose a model wherein the A and C rings of colchicine bind to beta-tubulin, while the B ring faces alpha-tubulin in the dimer.

Animals↗
PubMed1977

The enhancement by dietary zinc deficiency of the susceptibility of the rat duodenum to colchicine.

1. The incidence of colchicine-induced lesions in the germinal epithelium oof the rat duodenum was studied in young rats in an early stage of zinc deficiency and in their pair-fed controls. At both dose levels of colchicine used, a marked increase in the amount of cell damage was observed in the duodenum of Zn-deficient rats as compared with the pair-fed, control (Zn-supplemented) rats. 2. No statistical interaction between Zn and colchicine was demonstrable, and no lesions were found in the duodenum of animals that had not been treated with colchicine. 3. The results are discussed in relation to the effects of Zn deficiency in animals and the possible involvement of Zn in the maintenance of the integrity of microtubular structures.

Animals↗
PubMed2002

Determination of colchicine content in Colchicum hierosolymitanum and Colchicum tunicatum under cultivation.

Corms of Colchicum hierosolymitanum and Colchicum tunicatum were collected, identified and planted under field condition. We report here and for the first time the presence of colchicine in an appreciable amount in both species. The effect of different NPK fertilizer levels on colchicine content of the two Colchicum species at different growth stages were evaluated by HPLC. Results indicated that increasing NPK fertilizer levels significantly improve colchicine content in different plant parts and stages. The highest colchicine content observed in corms was at maturity stage 0.766 mg/g and 0.688 mg/g dry weight with C. hierosolimitanum and C. tunicatum, respectively.

Alkaloids↗
PubMedDate not supplied

Colchicine encapsulation within poly(ethylene glycol)-coated poly(lactic acid)/poly(epsilon-caprolactone) microspheres-controlled release studies.

Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Local delivery of agents capable of modulating vascular responses have the potential to prevent restenosis. However, the development of injectable microspheres for maintaining high tissue levels of drugs at the site of vascular injury is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, colchicine, in polyethylene glycol (PEG)-coated biodegradable microspheres composed of poly(lactic acid)/poly(epsilon-caprolactone) blends, with a mean diameter of 3-6 microm. A solution of colchicine and blends of polylactic acid (PLA)/polycaprolactone (PCL) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of PEG (or polyvinyl alcohol) with stirring by a high-speed homogenizer to form microspheres. Colchicine recovery in microspheres ranged from 30-50% depending on the emulsification system and the ratio of polymer blends used for the preparations. Scanning electron microscopy revealed that the PLA/PCL microspheres were spherical in shape and had a smooth surface texture. Results of in vitro release studies showed that it is possible to control the colchicine release by choosing the appropriate particle size, loading, and PLA/PCL composition. Water permeability through the PLA membrane was greater, when compared with PCL blends. The amount of drug release also was much higher (58.3%) in PLA compared with PCL (39.3%) microspheres, for 30 days. Therefore, we concluded that the drug release from the microspheres followed a diffusion mechanism where bulk erosion and surface deposition were negligible. These PEG-coated PLA/PCL microspheres may have potential for targeting antiproliferative agents for prolonged periods to treat restenosis.

Caproates↗
PubMed1968

The effect of colchicine on myogenesis in vivo in Rana pipiens and Rhodnius prolixus (Hemiptera).

The effect of colchicine on myogenesis in vivo has been studied in the regenerating tadpole tail of the frog, Rana pipiens, and in the abdominal molting muscles of a blood-sucking bug, Rhodnius prolixus Stål. Colchicine is shown to disrupt microtubules in the differentiating muscle cells of both these organisms. The disruption of microtubules is correlated with a loss of longitudinal anisometry in the myoblasts and myotubes of the regeneration blastema in the tadpole tail. Before colchicine treatment, the myotubes contain longitudinally oriented myofibrils. After colchicine treatment, rounded, multinucleate myosacs containing randomly oriented myofibrils are present. It is suggested that the primary function of microtubules in myogenesis in the Rana pipiens tadpole is the maintenance of cell shape. The abdominal molting muscles of Rhodnius undergo repeated phases of differentiation and dedifferentiation of the sarcoplasm. However, the longitudinal anisometry of the muscle fibers is maintained in all phases by the attachments of the ends of the fibers to the exoskeleton, and microtubule disruption does not alter cell shape. The orientation of the developing myofibrils is also unaltered, indicating that the microtubules do not directly align or support the myofibrils in this system.

Animals↗