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Effects of colchicine on the formation and looping of the tubular heart of the embryonic chick.

The role of microtubules in the early development of the chick embryo heart was studied. The microtubules were disrupted by treatment of the embryos with colchicine. The embryos were divided for study into three groups: (I) before the fusion of the paired cardiac primordia; (II) before the starting of the cardiac loop, and (III) during the formation of the looping process. Colchicine did not impair the fusion of the paired heart primordia nor the acquisition of an asymmetric C-shaped form. However, the normal counterclockwise movement of the heart loop was prevented. From these results we conclude that the formation of the tubular heart and its looping are independent of the integrity of the microtubular system. Under the effects of colchicine the developing myocytes rounded up bulging into the pericardial cavity. The cell contours became scarcely discernible and the individual cell surfaces gave rise to blebs and ruffles of different sizes. In older embryos, clefts of different sizes appeared between the myocardial cells. The effects of colchicine on the pulsatile activity of the heart were recorded. These effects, as well as those on the cell surface characteristics, were found to be age dependent. The more mature the hearts were, the more resistant to colchicine they became. The developmental significance of the results reported here is discussed.

Animals↗

Recurrent pericarditis. Relief with colchicine.

Recurrence is one of the major complications of pericarditis. Treatment of recurrence is often difficult, and immunosuppressive drugs or surgery may be necessary. We conducted an open-label prospective study of nine patients (seven men and two women; age, 18-64 years; mean age, 41.7 +/- 13.7 years). Patients were treated with colchicine (1 mg/day) to prevent recurrences. All patients had suffered at least three relapses despite treatment with acetylsalicylic acid, indomethacin, prednisone, or a combination. Pericarditis was classified as idiopathic in five patients, postpericardiotomy in two, post-myocardial infarction in one, and associated with disseminated lupus erythematosus in one. For statistical analysis, we conducted a paired comparison design (Student's t test). All patients treated with colchicine responded favorably to therapy. Prednisone was discontinued in all patients after 2-6 weeks (mean, 26.33 +/- 10.9 days), and colchicine alone was continued. After a mean follow-up of 24.3 months (minimum, 10 months; maximum, 54 months), no recurrences were observed in any patient; there was a significant difference between the symptom-free periods before and after treatment with colchicine (p less than 0.002). Our study suggests that colchicine may be useful in avoiding recurrence of pericarditis, although these results need to be confirmed in a larger, double-blind study.

Adolescent↗

Colchicine treatment for recurrent pericarditis. A decade of experience.

BACKGROUND: The most troublesome complication of acute pericarditis is recurrent episodes of pericardial inflammation, occurring in 15% to 32% of cases. The cause of the recurrence is usually unknown, although in some cases it may be traced to viral infection or may be a consequence of coronary artery bypass grafting. The optimal method for prevention has not been fully established; accepted modalities include nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressive agents, and pericardiectomy. METHODS AND RESULTS: Based on the proven efficacy of colchicine therapy for familial Mediterranean fever (recurrent polyserositis), several small studies have used colchicine successfully to prevent recurrence of acute pericarditis after failure of conventional treatment. Recently, we reported the results from the largest multicenter international study on 51 patients who were treated with colchicine to prevent further relapses and who were followed up for < or = 10 years. CONCLUSIONS: In light of new trial data that have accumulated in the past decade, we review the evidence for the efficacy and safety of colchicine for the prevention of recurrent episodes of pericarditis. Clinical and personal experience shows that colchicine may be an extremely promising adjunct to conventional treatment and may ultimately serve as the initial mode of treatment, especially in idiopathic cases.

Adult↗

Effect of colchicine on drug-induced changes in plasma renin concentration in rats.

Cytoplasmic microtubules appear to play a role in the secretion of a variety of protein and protein hormones. Involvement of microtubules in renin secretion has been hypothesized but not established. The present studies were designed to determine: 1) if the antimicrotubule drug, colchicine, would alter plasma renin concentration (PRC); and 2) if changes in PRC could be related to an effect on cytoplasmic microtubules. Dose response experiments in Sprague-Dawley rats showed that 0.4 or 0.8 mg/kg/day i.p. of colchicine for 3 days significantly increased PRC while a dose of 0.2 mg/kg/day was without effect. The increase in PRC at the higher doses was associated with toxicity of the drug. In other experiments, rats pretreated with colchicine (0.2 mg/kg/day) or saline received either furosemide (5 mg/kg) or isoproterenol (25 micrograms/rat) i.p. to stimulate renin secretion. Colchicine at a dose that did not alter basal PRC significantly inhibited an increase in PRC after stimulation with either isoproterenol or furosemide. Lumicolchicine, a structural isomer of colchicine without antimicrotubule activity, did not alter the response to isoproterenol stimulation. These data suggest that microtubules play a role in the increase in renin secretion following stimulation.

Animals↗

Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized prospective study. Members of the Lung Study Group.

Twenty-six symptomatic subjects with clinical evidence plus either high-resolution computed tomography (HRCT, n = 25) or open-lung biopsy (OLB, n = 1) patterns typical for idiopathic usual interstitial pneumonia (idiopathic UIP) were entered into a randomized prospective treatment trial using high-dose prednisone (n = 12) versus colchicine (n = 14). The minimum dose of prednisone used was 60 mg/d for 1 mo, tapered to 40 mg/d over the second month, tapered to 40 mg every other day during the third month, with subsequent doses adjusted as clinically indicated. The dose of colchicine was 0.6-1.2 mg/d, as tolerated. The presence of a rim of subpleural honeycomb change was present in all of the 25 subjects who had HRCT. Subjects treated with high-dose prednisone alone experienced a higher incidence of serious side effects and also exhibited a trend (not statistically significant, p = 0.391) to more rapid decline of pulmonary function and shortened survival than did those treated with colchicine alone. In most subjects with typical clinical and HRCT features of idiopathic UIP, neither prednisone nor colchicine resulted in objective improvement, and the disease continued to progress in the majority. Colchicine appears to be a safer alternative to a trial of high-dose prednisone but may be no different than no therapy.

Aged↗

Colchicine suppresses the release of fibroblast growth factors from alveolar macrophages in vitro. The basis of a possible therapeutic approach ot the fibrotic disorders.

Fibrosis is the accumulation of fibroblasts and the connective tissue products secreted by these cells, usually subsequent to tissue injury. While fibrosis can be useful in preserving the general structural integrity of a tissue, it often alters cell-cell and cell-connective tissue interactions, which leads to loss of tissue function. On the basis of the concept that mononuclear phagocytes can direct the development of fibrosis through the release of specific mediators that stimulate fibroblast proliferation, we propose a therapeutic strategy to prevent fibrosis by preventing the release of these specific mediators. The present study demonstrated that colchicine, a widely used and well-tolerated drug, can block alveolar macrophage release of 2 mediators associated with the development of fibrosis in interstitial lung diseases, fibronectin, and the alveolar-macrophage-derived growth factor (AMDGF). Colchicine blocked the spontaneous release of fibronectin by alveolar macrophages obtained from patients with fibrotic lung disease by 23 +/- 4% after 24 h and by greater than 90% after 72 h. AMDGF release was blocked by 68 +/- 10% after 4 h (p less than 0.01, all comparisons). The effect of colchicine was not due to nonspecific toxicity since [14C]proline tracer studies demonstrated that macrophages treated with colchicine were capable of de novo protein synthesis and the secretion of several protein products, despite the fact that fibronectin and AMDGF release were suppressed. The effect of colchicine on the spontaneous release of both fibronectin and AMDGF could be observed at concentrations less than 10 ng/ml, levels that can be achieved in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Colchicine↗

A controlled trial of colchicine to reduce the elastase load in the lungs of ex-cigarette smokers with chronic obstructive pulmonary disease.

A great deal of experimental evidence suggests that emphysema in smokers is caused by the action of neutrophil elastase on lung elastin. In order to test this hypothesis, it is necessary to find a drug that reduces the load of neutrophil elastase in the lungs of patients with emphysema. In a previous study we treated smokers with emphysema with colchicine, a drug that prevents neutrophil elastase secretion, to determine if it would reduce the elastase burden in the lungs. Colchicine was unable to reduce the elastase load while the stimulus of smoking continued. In this study we treated ex-smokers with emphysema to determine if colchicine could reduce the elastase burden in the lungs. The objective of the study was to determine if colchicine can reduce the elastase load and putative indicators of elastase load in the lungs of patients with chronic obstructive pulmonary disease. The study was a prospective, double-blind, randomized, and placebo-controlled clinical trial. The subjects were outpatients seeking treatment at the University of Texas Health Center at Tyler. We studied 16 ex-cigarette smokers between 45 and 75 yr of age with lung disease defined by FEV1 less than 70% of predicted but greater than 1.2 L whose airflow obstruction was less than 20% reversible with bronchodilators. Colchicine or placebo was taken by mouth in disguised capsules, 0.6 mg three times per day. Volunteers were placed on a baseline bronchodilator regimen of theodur by mouth and albuterol by inhalation. Blood, urine, and bronchoalveolar lavage fluids were obtained after 1 wk of stabilization.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Effects of colchicine and vinblastine on the cellular action of vasopressin in mammalian kidney. A possible role of microtubules.

To evaluate the possible role of microtubules in the cellular action of vasopressin on the mammalian kidney, the effects of microtubule-disrupting agents were studied in vivo and in vitro. In vivo studies were done in rats in mild to moderate water diuresis induced by drinking 5% glucose. Microtubule-disrupting alkaloids, colchicine (0.1 mg/day) or vinblastine (0.08 mg/day), given intraperitoneally, did not change water and solute excretion itself, but blocked or markedly inhibited the antidiuretic response (increase in urine osmolality and decrease in urine flow) to exogenous vasopressin. Total solute excretion was unaffected by these two alkaloids and there were no substantial changes in excretion of sodium, potassium, or creatinine. Lumicolchicine, a derivative of colchicine that does not interact with microtubules, did not alter the antidiuretic response to exogenous vasopressin. Activities of adenylate cyclase in the renal medullary plasma membrane, and cyclic AMP phosphodiesterase and protein kinase in renal medullary cytosol, were not influenced by 10(-5)-10(-4) M colchicine or vinblastine in vitro. Studies on the subcellular distribution of microtubular protein (assessed as [(3)H]colchicine-binding protein) in renal medulla shows that this protein is contained predominantly in the cytosol. Particulate fractions, including plasma membrane, contain only a minute amount (less than 6%) of the colchicine-binding activity. The results suggest that the integrity of cytoplasmic microtubules in cells of the distal nephron is required for the antidiuretic action of vasopressin, probably in the sites distal to cyclic AMP generation in the mammalian kidney.

Adenylyl Cyclases↗

Granulocyte-colony stimulating factor in the treatment of colchicine poisoning.

1. Colchicine is a highly active alkaloid used in the treatment of gouty arthritis and pseudogout. In overdose colchicine inhibits cell division effecting organs with a high rate of cell turn-over, such as the gastrointestinal tract and bone marrow. Early fatality results from cardiovascular collapse and respiratory failure, however pancytopenia and overwhelming septicaemia can occur later. 2. We describe a case of suicidal ingestion of 25-30 mg of colchicine in a previously healthy 43-year-old woman. Initial symptoms were mainly gastrointestinal. By day 5 she had developed severe pancytopenia and early sepsis, which were successfully treated using granulocyte colony stimulating factor (G-CSF) 600 micrograms s.c. 3. In vitro G-CSF is produced by the haematopoietic system. However, G-CSF can now be produced by recombinant DNA cloning technology and thus is available clinically. 4. There is no recognised antidote for colchicine poisoning and treatment is symptomatic. Fab fragments may have a promising future in eliminating colchicine from the body, but are currently not clinically available. In those patients that survive the initial phase of poisoning, G-CSF offers an effective method of treating the pancytopenia and preventing overwhelming septicaemia. Daily monitoring of the patient's haematological status is strongly recommended.

Adult↗

Cytochemical localization of calcium and Ca2+,Mg2(+)-adenosine triphosphatase in colchicine-altered rat incisor ameloblasts.

Colchicine is known to affect secretory, transport, and degradative functions of ameloblasts. The effects of colchicine on membrane-associated calcium and Ca2+,Mg2(+)-ATPase in secretory and maturation ameloblasts were investigated cytochemically. The pyroantimonate (PPA) method was used for localizing calcium and a modified Wachstein-Meisel medium was used to localize Ca2+,Mg2(+)-ATPase. Sections representing secretory and early maturation stages were examined by transmission electron microscopy. Morphological changes induced by colchicine included dislocated organelles and other well-established reactions to such anti-microtubule drugs. Calcium pyroantimonate (Ca-PA) deposits in most ameloblast types were markedly reduced, with the greater reduction occurring in those cells more severely altered morphologically. However, the cell membranes of both control and experimental smooth-ended maturation ameloblasts were essentially devoid of Ca-PA. The normal distribution and intensity of Ca2+,Mg2(+)-ATPase was not affected by colchicine. Because the observed reduction of membrane-associated calcium is apparently not mediated by Ca2+,Mg2(+)-ATPase in this case, other aspects of the calcium regulating system of ameloblasts are apparently targeted by colchicine.

Ameloblasts↗

Pituitary adenylate cyclase-activating peptide gene expression in corticotropin-releasing factor-containing parvicellular neurons of the rat hypothalamic paraventricular nucleus is induced by colchicine, but not by adrenalectomy, acute osmotic, ether, or restraint stress.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a newly discovered neuropeptide that is present in high amounts in hypothalamic neuroendocrine neurons and potently stimulates the accumulation of cAMP within cells of the anterior pituitary. We have employed several specific antisera recognizing different parts of the PACAP precursor to elucidate the distribution of PACAP-like immunoreactivities in the hypothalamic components of the hypothalamo-pituitary-adrenocortical axis in sections obtained from normal and colchicine-treated rats. Using immunohistochemistry with avidin-biotin-coupled peroxidase as a reporter system, high numbers of PACAP-immunoreactive perikarya were found in colchicine-pretreated rats in many of the parvicellular subdivisions of the hypothalamic paraventricular nucleus (PVN). A few cells were also found in the magnocellular subdivisions of the nucleus, and a similar small population of cells was observed in the dorsolateral aspect of the supraoptic nucleus. Using indirect immunofluorescence, the relation between CRF- and PACAP-containing neurons in the various parvicellular subnuclei of the PVN was studied, and a high degree of colocalization was demonstrated in the neurons of the medial parvicellular part of PVN. To further study the functional implications of PACAP in the hypothalamo-pituitary-adrenocortical axis, we examined the expression of PACAP messenger RNA (mRNA) in the PVN in response to five different stimulatory paradigms that previously have been shown to stimulate CRF mRNA expression in the medial parvicellular part of the PVN. The stimulatory challenges of adrenalectomy, restraint stress, ip injection of hypertonic saline, ether stress, and intracerebroventricular injection of colchicine induced significant elevations of CRF mRNA expression in the medial parvicellular part of the PVN. In contrast, the expression of PACAP mRNA, which is hardly detectable within the medial parvicellular part of the PVN, was induced only by colchicine treatment (from undetectable levels to 177 +/- 21 dpm/g; mean +/- SEM), whereas PACAP mRNA remained undetectable in this region of the PVN after exposure to any of the other stimulatory paradigms. The onset of colchicine-induced PACAP mRNA expression in the PVN was rapid (3 h), and PACAP mRNA levels remained elevated throughout the 48-h observation period. Considering the different topography and connections of the parvicellular subnuclei of the PVN, the current observations suggest that PACAP present in parvicellular neurons of the PVN may act not only as a neuroendocrine transmitter/modulator in the hypothalamo-pituitary-adrenocortical axis, but also as transmitter mediating neurotransmission conveyed from the PVN to preganglionic neurons of the autonomic system.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex↗

Meiotic telomere clustering is inhibited by colchicine but does not require cytoplasmic microtubules.

Telomere clustering, the defining feature of the bouquet, is an almost universal feature of meiotic prophase, yet its mechanism remains unknown. The microtubule-depolymerizing agent colchicine was found to inhibit bouquet formation. Telomeres in colchicine-treated cells remained scattered in the nuclear periphery, whereas untreated cells exhibited a prominent telomere cluster. Colchicine administered after the bouquet had formed did not affect telomere dispersal. The effect of colchicine on bouquet formation appeared to be separable from its effect on cytoplasmic microtubules; amiprophos methyl, a highly effective plant microtubule-depolymerizing drug, did not affect telomere clustering. Inhibition of bouquet formation was limited to colchicine and the related drug podophyllotoxin out of the variety of microtubule-depolymerizing drugs tested, suggesting that the target involved in bouquet formation has a structural specificity.

Cells, Cultured↗

Colchicine resistance in mammalian cell lines.

Colchicine-resistant variants derived from mouse and Syrian hamster lines are described. The resistant cells do not appear to be true mutants, since they appear at a high frequency, unaffected by treatment with ethyl methyl sulphonate, and are unstable in the absence of the drug. They are cross-resistant to other drugs, show a reduced rate of binding of colchicine in monolayer, and give extracts with colchicine-binding properties identical to those of the wild type. Thus the resistance is due to a permeability barrier. The naturally occurring resistance of the Syrian hamster line is specific for colchicine, and may be due to a specific permeability barrier. The Syrian hamster line is also shown to have an extra colchicine-binding pool.

Animals↗

Inhibitory effect of ethanol and colchicine on the intracellular processing of beta-glucuronidase which occurs in the Golgi complex.

To investigate the effect of ethanol or colchicine on the intracellular proteolytic processing of lysosomal beta-glucuronidase, which is considered to occur in the Golgi complex in the intracellular sorting pathway, three rat liver Golgi subfractions, GF-1, GF-2, and GF-3, were isolated from ethanol- or colchicine-treated rats, and the electrophoretic patterns of the extracted Golgi beta-glucuronidase on polyacrylamide gel were examined. The isolated Golgi subfractions from the drug-treated rats gave a better yield of fraction than that from the control rats. The enzymatic characterization of these three subfractions showed no significant contamination by other subcellular structures such as plasma membranes, microsomes, or lysosomes, and no inhibitory effect of the drugs was observed. On the other hand, suppressed galactosyltransferase activity, a marker enzyme of the Golgi complex, was detected in the colchicine-treated rats. The electrophoretic pattern of Golgi beta-glucuronidase on polyacrylamide gel revealed one major band which moved to the same position as the lysosomal enzyme type in the control rats. In contrast, in the ethanol- and colchicine-treated rats, Golgi beta-glucuronidase was found to have two major bands stained for enzyme activity resulting from a mixture of microsomal- and lysosomal-type enzymes. These results suggested that the post-translational modification step, during conversion from a microsomal-type enzyme to a lysosomal-type enzyme, was apparently inhibited. Taken together, these findings indicated that ethanol or colchicine administration to rats caused an inhibitory effect on the intracellular post-translational modification of Golgi beta-glucuronidase destined for targeting to the lysosomes.

Animals↗

Rhabdomyolysis associated with gemfibrozil-colchicine therapy.

OBJECTIVE: To report a case of rhabdomyolysis possibly due to combination therapy with colchicine and gemfibrozil. CASE SUMMARY: A 40-year-old man with amyloidosis and hepatitis B virus-related chronic liver disease was admitted to the university hospital because of fatigue, lack of appetite, dark brownish urine, and myalgia for 2 weeks. The patient was receiving colchicine and gemfibrozil. Elevations of serum creatine kinase, lactate dehydrogenase, and aspartate aminotransferase concentrations with myalgia were compatible with the diagnosis of rhabdomyolysis. DISCUSSION: To our knowledge, myopathy and rhabdomyolysis due to a combination of colchicine and gemfibrozil therapy have not been previously reported. Preexisting mild renal failure, hepatitis B-related chronic liver disease, and amyloidosis may be contributing risk factors for the development of rhabdomyolysis in this patient. An objective causality assessment revealed that the adverse drug event was possible. CONCLUSIONS: Patients receiving combination therapy with colchicine and gemfibrozil, especially those with renal and hepatic dysfunction, should be monitored for rhabdomyolysis, and concomitant colchicine and gemfibrozil therapy should be considered in the differential diagnosis of rhabdomyolysis.

Adult↗

Colchicine in the treatment of pulmonary fibrosis.

There is no standard or known optimal treatment for idiopathic pulmonary fibrosis. Corticosteroids have been used with widely variable benefit. Colchicine has been reported to suppress fibroblast growth factors and to inhibit collagen deposition. A potential role has been proposed for colchicine in the treatment of fibrotic pulmonary diseases. We retrospectively assessed the outcome of 23 patients with idiopathic pulmonary fibrosis in whom colchicine was used as empiric treatment. Eighteen patients had received prior corticosteroid therapy. By clinical and pulmonary function criteria, five patients (22 percent) improved following colchicine, nine (39 percent) remained stable, and nine (39 percent) worsened. The average duration of follow-up was 22 months. Despite limitations of this retrospective analysis, colchicine may be of benefit in pulmonary fibrosis and should be considered for further clinical trials.

Adult↗

The effect of pH on colchicine conformation and structure.

The effect of various pH values between 0 and 14 on the structure and conformation of colchicine was examined using UV-vis spectrophotometry at a concentration of 1.7 x 10(-5) M and NMR techniques at a colchicine concentration of 0.1M. The complete interpretation of the colchicine NMR spectrum in D2O is given. A stable structure of the colchicine molecule in aqueous solutions at pH from 2 to 12 was demonstrated. However, during incubation at 40 degrees C colchicine was found to be stable only at pH values between 2 and 10. The significance of these data for reactions of cholchicine in regard to metabolism and interaction with macromolecules is discussed.

Colchicine↗

Familial Mediterranean fever and growth: effect of disease severity and colchicine treatment.

OBJECTIVE: To evaluate the effect of disease severity and colchicine treatment on height and weight parameters in children with familial Mediterranean fever (FMF). METHODS: Thirty prepubertal children (19 M, 11 F) were studied retrospectively. Z-score values of height, growth velocity, weight and body mass index were obtained over 1.84 +/- 1.14 years before and 2.58 +/- 1.55 years during colchicine therapy. Disease severity was evaluated by a specific score for FMF. RESULTS: By comparison to growth before treatment, during colchicine therapy height SDS increased from -1.00 +/- 1.17 to -0.54 +/- 0.96 (p < 0.001) and weight SDS increased from -0.74 +/- 1.09 to -0.47 +/- 1.06 (p = 0.008). An effect of disease severity on growth pattern could not be detected. Height SDS during therapy was negatively correlated with age at colchicine initiation. CONCLUSIONS: Colchicine therapy has a positive effect on both height and weight parameters in children with FMF. Early initiation of treatment is beneficial for height gain.

Anti-Inflammatory Agents↗