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[Colchicine treatment of recurrent steroid-dependent pericarditis in a patient with post-myocardial-infarction syndrome (Dressler's syndrome)].

The usual treatment of pericarditis consists of non-steroid anti-inflammatory agents. In cases where the symptoms and/or the pericardial effusion persist or progress, the disease can be arrested in the majority of cases by employing steroids. In some patients, it may prove difficult to conclude steroid treatment as gradual withdrawal results in recurrence and it may, therefore, be necessary to continue with large doses of steroid for prolonged periods. There is, however, a possibility for another form of treatment. The present authors present the case history of a patient with pericarditis on the basis of the post-myocardial-infarction syndrome and in whom the symptoms recurred several times during attempts at gradual withdrawal of prednisolone. Treatment with colchicine was commenced. The patient rapidly became symptom free and has now been symptom free for 45 weeks without prednisolone. Colchicine was withdrawn after 33 weeks without recurrence. It is considered that trial of colchicine treatment can be recommended in cases of recurring pericarditis particularly when there are problems (recurrence) on attempted withdrawal of steroid treatment. Naturally, it is important to exclude specific causes requiring other forms of treatment as the cause of the pericarditis (e.g. malignant disease, tuberculosis, systemic disease etc.).

Colchicine↗

Th1 cytokine pattern (IL-12 and IL-18) in bronchoalveolar lavage fluid (BALF) before and after treatment with interferon gamma-1b (IFN-gamma-1b) or colchicine in patients with idiopathic pulmonary fibrosis (IPF/UIP).

BACKGROUND AND AIM: Characterization of the biologic effects of Th1 cytokines will enhance the understanding of idiopathic pulmonary fibrosis (IPF) pathogenesis and treatment selection. Th1 response is characterized by increased expression of IFN-gamma, interleukin (IL)-12 and IL-18. The present study aims to evaluate the role of Th1 cytokines and their possible changes in the bronchoalveolar lavage fluid (BALF), before and after treatment with IFN-gamma-1b or colchicine. PATIENTS AND METHODS: We studied prospectively 10 patients (8 male, 2 female) of median age 67 yr with histologically confirmed IPF/UIP. Patients were randomly assigned to receive either IFN-gamma-1b 200 microg sc (5 patients) or colchicine 1 mg qd (5 patients) plus prednisone 10 mg qd. BALF IL-12 and IL-18 levels were measured before and after treatment. RESULTS: BALF IL-12 levels before and after treatment did not differ significantly between the two treatment groups. However, BALF IL-18 levels were significantly decreased after treatment with IFN-gamma-1b (mean +/- SD, 58.4 +/- 15.6 pg/mL vs 42.8 +/- 4.90 pg/mL, p < 0.05). A significant difference was also found after treatment with colchicine (mean +/- SD, 66.8 +/- 36.9 pg/mL vs 42.6 +/- 1.08 pg/mL, p < 0.01). A significant correlation was found between IL-18 BALF levels and the BALF neutrophils (r = 0.75, p = 0.024). CONCLUSION: Our data suggest the potential role of IL-18 as an inflammatory marker in the pathogenetic pathway of IPF such as its possible downregulation by IFN-gamma-1b treatment. Further studies are needed in a higher number of patients in order to define the precise role of both cytokines during the immunoregulatory response with IFN-gamma-1b.

Aged↗

Treatment with colchicine decreases white cell counts in synovial fluid of asymptomatic knees that contain monosodium urate crystals.

Synovial fluid (SF) samples, all containing monosodium urate crystals, obtained from 18 asymptomatic knees of 12 patients with gout, were serially analyzed before and one month after treatment with 1 mg/day of oral colchicine. Before treatment, the SF contained 612 [confidence limits (CL) = 282, 942] cells/mm3, while after treatment these values decreased to 274 (CL = 73, 471) cells/mm3 (p less than 0.005). In all cases, pretreatment cell counts were higher than the corresponding posttreatment values. The percentage of polymorphonuclear leukocytes also diminished from a pretreatment value of 13.0 (CL = 7, 19) to 4.5 (CL = 2, 7) after colchicine administration (p less than 0.005). These results strongly suggest the presence of baseline subclinical joint inflammation which is reduced by colchicine. The preventive effect of this drug on the occurrence of new attacks may relate to its effect in reducing the baseline inflammation of the asymptomatic joints.

Colchicine↗

In-vivo identification of tumor multidrug resistance with 3H-colchicine [corrected].

Multidrug resistance (MDR) is a major obstacle in the clinical treatment of cancer with natural-product anticancer agents. Identification of MDR in vivo could be important in the design of chemotherapeutic regimens. As a first step in developing radiolabeled drugs to detect MDR, we measured the in vivo distribution of radiolabel from [ring C, methoxy-3H]-colchicine ([3H]-CHC) in immunosuppressed mice bearing xenografts of colchicine-resistant and sensitive tumor cell lines. Experiments were done at trace (1 microgram/kg) and LD50 (4 mg/kg) dose levels. Activity concentration/injected dose was more than twice as great in sensitive as in resistant tumors (p less than 0.01) at 60 min following retroorbital injection of [3H]-CHC. There was no significant difference in activity distribution between trace- and high-dose injections for any of the tissues sampled. Chromatographic analysis of plasma and tumor extracts demonstrated extensive extravascular metabolic degradation of [3H]-CHC. The ratio of [3H]-CHC concentration of injected dose between sensitive and resistant tumors was 3:1 (p less than 0.05), due primarily to protein-bound [3H]-CHC. This preliminary study demonstrates that it is possible to distinguish multidrug resistant from sensitive tumors in vivo on the basis of radiolabel uptake from an injected MDR drug. Colchicine, labeled with 11C at the [ring C]-methoxy group, may be useful as a radiopharmaceutical for quantitative identification of MDR in human tumors using PET.

Animals↗

The medical and surgical treatment of finger clubbing and hypertrophic osteoarthropathy. A blind study with colchicine and a surgical approach to finger clubbing reduction.

In fourteen patients affected with pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy, the efficacy of colchicine (0.5 mg day for one month) versus placebo on the main clinical features of the disease (finger clubbing, arthritis and pachydermia) was evaluated. In addition, in one patient the usefulness of surgical reduction of clubbed fingertips was investigated. Colchicine did not demonstrate any appreciable effect on finger clubbing (expressed in degrees) or pachydermia, while an effect on arthralgia (as evaluated by the Ritchie Index and Pain Scale) was observed. The surgical treatment of clubbed fingertips failed to show a satisfactory and stable reduction of the fingertips; two months after surgery the nail matrix apparently produced new tissue, once again enlarging and deforming the finger. These results suggest that low dose colchicine cannot be considered the drug of first choice for the treatment of PDP, while higher dosages, although effective, are not tolerated because of the severe side effects. An effective medical and surgical treatment for PDP will be found only when the pathogenetic mechanisms of the disease are clarified.

Adult↗

[The effect of colchicine on the periodicity of the spontaneous and induced respiratory burst of granulocytes and monocytes during familial Mediterranean fever].

The influence of colchicine on the spontaneous and chemotaxis-, protein kinase C-, and phagocytosis-induced respiratory burst of neutrophils and monocytes in the peripheral blood of patients with familial Mediterranean fever (FMF) has been studied. The transient activation of neutrophils and monocytes on the level of a single cell has been monitored by means of flow cytofluorimetry. It is shown that colchicine blocks the induction of chemotaxis-, phagocytosis-, and proteinkinase C-dependent respiratory burst in vitro, as well as the increased pro-oxidant transient activation of neutrophils and monocytes of FMF patients, both in the period of remission and during the FMF attack. Colchicine stimulates the intensity of the spontaneous respiratory burst of neutrophils and monocytes in patients in the course of remission and during the FMF attack. At the same time, the drug effectively suppresses the periodicity of the multidirectional transient activation of the respiratory burst of effector cells during FMF.

Adolescent↗

Colchicine-induced redistribution of proton pumps in kidney epithelial cells.

In kidney medulla, intercalated cells (ICs) all have an apical proton-pumping ATPase, but in the cortex, ICs with apical (type A cells) and basolateral (type B cells) proton pumps coexist. Proton pumps in proximal-tubule epithelial cells are located in a band of apical membrane at the base of the brush border. To determine the effect of microtubule disruption on proton-pump polarity in these cell types, we immunolocalized proton pumps in normal and colchicine-treated rat kidneys. In addition, NEM-sensitive ATPase was measured in brush-border (BBMV) and basolateral membrane vesicles from kidney cortex. Rats were injected with colchicine, and kidneys were fixed 4-24 h later. In both cortical and medullary IC, proton pumps were localized on vesicles that were scattered throughout the cell. A- and B-type ICs were no longer distinguishable on the basis of proton-pump polarity. In the medulla, no concentration of proton pumps at the basolateral pole of ICs was detectable. In proximal tubules, pumps were also scattered on vesicles throughout the cytoplasm. NEM-sensitive ATPase was reduced by over 60% in BBMV, and was also reduced in basolateral membranes, indicating no increased insertion of NEM-sensitive ATPase into basolateral membranes after colchicine treatment. We conclude that a change in the polymerization state of microtubules is not sufficient to account for the differential targetting of proton pumps in subpopulations of intercalated cells.

Adenosine Triphosphatases↗

[Effect of colchicine on rat neuromuscular transmission].

The function of the microtubules (MTs) beneath the postsynaptic membrane was studied in the isolated non-uniform stretched muscle preparation of rat diaphragm with the use of colchicine. After exposure to this drug, the amplitude of miniature endplate potential (MEPP), the mean quantal contents and mean amplitude of endplate potentials (EPPs) elicited by 10 Hz and 50 Hz stimulation and the amplitude of acetylcholine potentials (AChP) were decreased significantly, but the frequency of MEPP, membrane potential and the time course of EPP and AChP remained unchanged. These results indicate that colchicine suppresses the responses of acetylcholine receptors (AChR). No such effects were observed with colchicine's isomer lumicolchicine. It is suggested that the MTs beneath the postsynaptic membrane may be involved in the responsive process of AChR.

Animals↗

[Evaluation of the genotoxicity of vincristine and colchicine using mouse lymphoma tk mutation assay].

OBJECTIVE: To evaluate the genotoxicity of two mitotic inhibitors vincristine and colchicine, and to compare the detecting sensitivity of tk gene mutation assay with short-and long-term treatment by them. METHODS: Tk gene mutation assay was performed by microwell method with L5178Y mouse lymphoma cell line after exposing to vincristine and colchicine for 3 h and 24 h respectively, and the results of two different treating time were compared. RESULTS: The two chemicals didn't show positive responses in mouse lymphoma assay (MLA) with 3h treatment, but they could induce tk mutation frequency increase 1.6 to 4.8 and 2.1 to 6.2 times higher to spontaneous MF respectively after continuous treatment for 24 h. CONCLUSION: Vincristine and colchicine had mutagenic effect on tk gene with long-term treatment, which indicated that the detecting sensitivity of MLA could be enhanced by long-term treatment.

Animals↗

The pharmacologic basis of treatment with colchicine in children with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the prototype of auto-inflammatory disorders and is ethnically restricted to people living in the Mediterranean basin and Middle-East. Pyrin, the protein product of the FMF gene, expressed in myeloid cells and fibroblasts, interacts with the cytoskeletal machinery and may modulate leukocyte effector functions. At present colchicine, an alkaloid with antimitotic activity interfering with microtubule formation, which has been used to alleviate acute gout, is the only available drug for patients with FMF to prevent both acute attacks and long-term complications such as amyloidosis. The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules, but also through changes at the transcriptional level influencing cell cycle regulation and leukocyte migration. Gastrointestinal side effects may occur early and are the most frequent manifestations of colchicine toxicity in children, whilst multiple organ failure is very rarely reported as overdosage expression.

Amyloidosis↗

Independent alterations in cell shape and intramembranous particle topography induced by cytochalasin B and colchicine in normal and transformed cells.

Native differences in cell shape and plasma membrane organization in contact-inhibited and transformed cells and the effects of cytochalasin B and colchicine on these cells have been examined by scanning electron microscopy and freeze fracture-electron microscopy. Confluent BALB/c 3T3 cells show a flat, polygonal shape with limited cell overlapping, some microvilli, and plasma membranes with an aggregated distribution of intramembranous particles. Simian virus 40-transformed BALB/c 3T3 cells, by contrast, have a pleomorphic, bipolar spindle shape, extensive cell overlapping, more numerous surface projections, and a random distribution of intramembranous particles. Treatment of 3T3 and SV3T3 cells with 10(-6) M colchicine produced changes in cell shape and induced intramembranous particle aggregation in SV3T3 cells but did not significantly affect the freeze fracture morphology of 3T3 plasma membranes. Treatment of 3T3 and SV3T3 cells with cytochalasin B (1 mug/ml) also produced marked changes in cell shape and induced intramembranous particle disaggregation in 3T3 cells, but it did not affect intramembranous particle distribution in SV3T3 cells. Lower doses of colchicine (10(-9) M) or cytochalasin B (1 to 50 ng) modulated intramembranous particle distribution in transformed and normal 3T3 cells, respectively, without seriously affecting cell shape. These results are interpreted to suggest that modulation of cell shape or cell surface topography and intramembranous particle distribution are separable phenomena.

Animals↗

[The potentials of colchicine in the combined therapy of secondary amyloidosis in patients with rheumatoid arthritis].

The authors relate the results of prolonged treatment (up to 3.5 years) with colchicin of 22 patients suffering from rheumatoid arthritis (RA) complicated by morphologically verified secondary amyloidosis of the kidneys and/or of the gingival, rectal and hepatic mucosae. Colchicin prescribed as the only slowly acting agent turned out effective in 5 out of 11 patients and in all the 11 patients given the drug in combination with basic therapy by cytostatics or, rarely, by gold drugs and D-penicillamine. The treatment efficacy could be observed both in respect to the manifestations of rheumatoid disease proper and in respect to the manifestations of amyloidosis. The drug did not produce any side effects and could be administered for a long time. In the overwhelming majority of cases, the withdrawal of colchicin, even in basic therapy continuation caused the enhancement of the manifestations of RA and amyloid nephropathy.

Amyloidosis↗

The combination of prednisone and colchicine in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of the biliary tract. The cause of the disease is unknown, and no effective medical treatment exists. In this study, 12 patients received a combination of low-dose prednisone (10 mg/day) and colchicine (0.6 mg bid). Their course was compared with that of a group of concurrent historical controls. At 6 and 12 months, there was significantly more improvement in liver test results over baseline values in patients receiving prednisone and colchicine than in the untreated controls. At 24 months, however, no significant differences in biochemical tests were appreciated between treated and untreated patients. Analysis of serial liver biopsies showed no differences in histologic change in the two groups. During the 2 yr of follow-up, there were two deaths in the control group but none in the treated group. Four untreated patients developed ascites; gastrointestinal bleeding developed in three untreated patients, one of whom developed ascites. In contrast, in the treated group, ascites and bleeding developed in only one patient. We conclude that the combination of colchicine and prednisone does not retard histologic progression or progression of standard liver tests after 2 yr of therapy. There is a trend toward less clinical deterioration and improved survival after 2 yr of treatment. On the basis of these findings, we would not advocate empiric use of these drugs for patients with primary sclerosing cholangitis, but suggest that, if they are to be used at all in PSC, they be evaluated in a controlled clinical trial as treatment for this as yet incurable disease.

Adult↗

Distinct colchicine binding kinetics of bovine brain tubulin lacking the type III isotype of beta-tubulin.

In mammalian brain, beta-tubulin occurs as a mixture of four isotypes designated as types I, II, III, and IV. It has been speculated in recent years that the different tubulin isotypes may confer functional diversity to microtubules. In an effort to investigate whether different tubulin isotypes differ in their functional properties we have studied the colchicine binding kinetics of bovine brain tubulin upon removal of the beta III isotype. We found that the removal of the beta III isotype alters the binding kinetics from biphasic to monophasic with the disappearance of the slow phase. The kinetics become biphasic with the reappearance of the slow phase when the beta III-depleted tubulin was mixed with the beta III fraction eluted from the affinity column with 0.5 M NaCl. The analysis of the kinetic data reveals that the tubulin dimers containing beta III bind colchicine at an on-rate constant of 35 M-1 s-1 while those lacking beta III bind at 182 M-1 s-1. Our results strongly suggest that the beta-subunit plays a very important role in the interaction of tubulin with colchicine.

Animals↗

Kinetics of dissociation of the tubulin-colchicine complex. Complete reaction scheme and comparison to thermodynamic measurements.

The slow dissociation reaction of the tubulin-colchicine complex has been characterized in purified calf brain tubulin and microtubule protein preparations, using [3H]colchicine and fluorometric measurements. It fits to a single exponential phase, within the accuracy of these measurements. The dissociation is a kinetically unfavorable reaction, with activation energy values of 114 +/- 10 and 94 +/- 10 kJ mol-1 (purified tubulin and microtubule protein, respectively). The kinetic scheme previously proposed for the tubulin-colchicine association (Lambeir, A., and Engelborghs, Y. (1981) J. Biol. Chem. 256, 3279-3282) is: T + C K1 in equilibrium TC k2 in equilibrium k-2 (TC)' where step 1 is a fast reversible binding and step 2 is a slow conformational change, whose backward rate constant (k-2) was neglected for the association study. This kinetic scheme has now been completed to include the measurements of the rate-limiting dissociation step (k-2), and of the purified calf brain tubulin preparation. The overall binding standard free energy change, calculated from the kinetic measurements, is -42.0 +/- 0.1 kJ mol-1 (fast phase of binding in 10 mM sodium phosphate buffer, 0.1 mM GTP, pH 7.0, at 37 degrees C). The binding is exothermic and the calculated enthalpy change is -26 +/- 13 kJ mol-1, which coincides with the recently determined calorimetric enthalpy value, -21 +/- 2 kJ mol-1 (Menendez, M., Laynez, J., Medrano, F. J., and Andreu, J. M. (1989) J. Biol. Chem. 264, 16367-16371), suggesting that the kinetic scheme and measurements are essentially correct.

Animals↗

Colchicine binding to tubulin from brain homogenates in the presence of sugars, glycols and metal ions. Effect of nickel ions on the tubulin solubility.

The fact that glycerol preserves microtubules from depolymerizing in vitro, and that some ions such as Ca(II) and Mg(II), regulate the assembly-disassembly process of these structures, induced us to study the effect of several sugars, glycols and metal ions on solubility and colchicine affinity of tubulin in rat brain homogenates, and of purified microtubular protein. Inhibition of colchicine binding was significant with glycerol, polyethylene glycol 1000 (PEG-2) and the ions Al(III), Co(II), Ni(II), while compounds structurally related to glycerol (glucose and sucrose) did not inhibit it. Mannitol, instead, increased the activity a 47% over control. Apparently the presence of some compounds in brain homogenates [PEG-2 (1000) and Ni(II)] favored tubulin sedimentation when these latter were centrifuged at 100,000 x g for 150 min at 20 degrees C, but the form in which tubulin becomes aggregated in the pellet is unknown. Nickel ion made insoluble microtubular protein of homogenates and the purified one by more than 90% without causing significant inhibition of the colchicine binding. The sediment containing nickel-treated two cycles purified microtubular protein observed with the electron microscope did not present microtubules, but it revealed the presence of irregular, wavy and stretched structures bearing highly dense dotted material. The sediments became soluble in phosphate-glutamate buffer (pH 6.8) and, when incubated in polymerizing conditions, gave rise to microtubules undistinguishable from those prepared with untreated purified protein.

Aluminum↗

[Multi-organ failure caused by colchicine poisoning].

A 61-year-old woman was admitted because of colchicine intoxication. After a period with gastrointestinal symptoms multiple organ failure and secondary septicaemia developed. The patient died of irreversible shock. The pharmacology of colchicine and the clinical manifestations and therapy of colchicine intoxication are discussed.

Colchicine↗

[The effect of colchicine and its derivatives on the activity of enzyme markers of T-lymphocytes].

Colchicine and its less toxic derivatives (demecolcine and deacetyl colchicine), in dependence on the concentration in the incubation medium, inhibited the activity of adenosine deaminase in the lymphocytes. All the three substances increased the level of cyclic adenosine monophosphate which has the ability of influencing the proliferation of T-lymphocytes. Colchicine and its derivates also inhibited the activity of purine nucleooxidophosphorylase, which, similarly as adenosine deaminase, is a marker enzyme of T-lymphocytes. The results obtained lead to the assumption that the mentioned preparations inhibit the function of T-lymphocytes.

Adenosine Deaminase↗