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Two cases of suicide involving colchicine are examined. Colchicine and colchicum preparations have been used for the relief of pain in acute gout and are reported to be effective for the treatment of periodic peritonitis. A method using enzymatic digestion, extraction, and high pressure liquid chromatographic analysis for the extraction and analysis of colchicine in autopsy specimens is described.
The studies were carried out to examine the role of microtubules and microfilaments on bile secretion in the rat in vivo. Phalloidin (which causes irreversible polymerization of actin into microfilaments), administered at the dose of 50 microgram/100 g body wt during 3 days, caused an increase in the microfilamentous network around bile canaliculi; it induced a significant decrease both in basal bile flow, and in bile flow stimulated by sodium taurocholate, the major bile acid in the rat. Colchicine (which inhibits the polymerization of tubulin into microtubules), 3 hr after an injection of 0.2 mg/100 g body wt, caused the almost complete disappearance of microtubules in the hepatocytes; it did not modify basal bile secretion, but did induce a significant decrease in taurocholate secretion and taurocholate-stimulated bile flow after a bile-acid load, as well as a delayed plasma disappearance of the bile acid. Lumicolchicine, which is known to have no effect on tubulin, had no effect on bile secretion. The combined administration of phalloidin and colchicine caused both the increase of the pericanalicular microfilamentous network and the disappearance of microtubules; it induced a decrease in basal bile flow that was more marked than that observed with phalloidin alone, suggesting that the effects of the two drugs were not simply additive, but synergic. Although a toxic effect of colchicine could not be totally excluded, the results are compatible with the hypothesis that microtubules as well as microfilaments play a role in the excretion of a bile-acid load.
The genetic nature of the resistance of mouse L cells to 0.06 microgram/ml of colchicine (the first step of selection) was studied. Fluctuation tests showed that the generation of drug-resistant variants in the wild type population was random and did not depend on the action of the selective agent. The rate of spontaneous occurrence of this variants was approximately 2 . 10(-5) per cell per generation. Colchicine resistance proved to be relatively unstable: it was 2--3-fold less in all clones propagated in non-selective conditions for 25--33 days. Two mutagens, ethylmethanesulphonate and N-nitroso-N-methylurea, failed to induce colchicine resistance in conditions when they enhanced the frequency of 8-azaguanine-resistant cells 10-fold.
The effect of phenobarbital on vincristine and colchicine antimitotic activity has been studied. The number of mitotic figures present in the rat bone marrow and Galeazzi-Lieberkühn cripts has been used to evaluate the overall proliferative activity of these cell populations. The administration of phenobarbital brought a reduction in the percentage of arrested mitoses in rat bone marrow and intestinal glands after treatment with vincristine and colchicine. Parallel studies on the phenobarbital effect on the LD50 and LD100 of vincristine and colchicine confirmed a decreased toxicity of these agents in the animals pretreated with phenobarbital.
Colchicine (1 approximately 2 X 10(-5) M), a microtubule inhibitor, was added to the organ cultures of rat crystalline lenses. 1. Wistar rats weighing 60-70 grams were used. Their crystalline lenses were cultured and the development of posterior subcortical cataracts became grossly evident in the 4-day-old culture. Corresponding to the posterior subcortical opacity which was macroscopically apparent, vacuole formation was noted in the posterior subcortical region under light microscopy. Layers of bladder cells also existed at the equator. 2. An organ culture was prepared from lenses of Wistar rats weighing 14 grams. On the second day, microtubules were observed in the epithelial cells and lens fibers of the control (normal) lens. In the colchicine (1 X 10(-5) M)-treated cataractous lenses, however, microtubules had disappeared both in the epithelial cells and in the lens fibers on the second day. The above findings suggested that the loss of microtubules had a significant effect on lens opacity in colchicine (1 X 10(-5) M)-treated experimental cataracts in vitro.
A method of local application of colchicine deposited in a wax and paraffin alloy to the nerve is suggested. The doses of 25, 50, 75 and 100 micrograms were tested. Four days after application of 75 and 100 micrograms of colchicine, light microscopy demonstrated a non-uniform thickening of neurofibrils and the increase in their argyrophilic properties. Electron microscopy discovered the reduced number of microtubules, disordered arrangement of neurofilaments and accumulation of the latter ones beneath the neurolemma. The overall electric activity of the nerve was not disturbed. The method of colchicine application in vivo ensures the prolonged action of the drug without nerve compression or injury, thereby enabling one to assess consistently the sequels of the blockade of neurotrophic factors for metabolism of the innervated structures.
Thioglycollate-elicited mouse peritoneal macrophages were cultivated in vitro and endocytosis of native and cationized horseradish peroxidase was studied electron microscopically and biochemically. Native peroxidase (HRP) was ingested by fluid-phase endocytosis and accumulated in lysosomes. Cationized peroxidase (CHRP) bound diffusely to the macrophage surface in a saturable manner. It was then internalized via membrane folds and transferred not only to lysosomes but also to the Golgi complex, mainly those parts referred to as GERL and positive for acid phosphatase activity. Following initial uptake, surface staining for CHRP was lost, although the tracer remained present in the medium. This indicates that anionic binding sites were internalized together with the ligand and not immediately replaced. Accordingly, continued uptake of CHRP occurred at a rate similar to that for HRP. Exposure of the macrophages to cationized ferritin (CF) decreased their ability to bind CHRP. However, after 2 to 4 h in CF-free medium, the CHRP-binding ability returned and raised to 2 to 3 times higher values than in cells not exposed to CF. Treatment with cycloheximide at a concentration that effectively inhibits protein synthesis did not clearly affect this regeneration. These findings support the concept of recirculation of plasma membrane constituents. They further suggest that there exists an intracellular membrane pool which rapidly exchanges with the cell surface. Colchicine removed cytoplasmic microtubules, caused a characteristic disorganization of the Golgi complex, and inhibited uptake of both HRP and CHRP. Additionally, no transport of CHRP to the Golgi complex or GERL was observed in colchicine-treated cells. The regeneration of surface anions after exposure to CF was also delayed. Contrarily, lumicolchicine was without effect on cell morphology and uptake as well as intracellular transport of the tracers. Nevertheless, the effects of colchicine on endocytosis were not necessarily due to a direct role of microtubules. They could be secondary to a disturbed function of the Golgi complex or other organelles after collapse of the microtubular cytoskeleton.
A 35-year-old man, sephardic jew, complains for the last eleven years of typical and frequent attacks of FMF. His liver is hypertrophic. Needle-biopsy reveals an extensive macrovacuolar triglyceride storage (60 per cent) and an active vascular congestion with erythrodiapedesis in the mild and centrolobular zone, without any necrosis, cellular infiltration nor fibrosis. Electron microscopy shows lipofuschin deposits and mild lesions of mitochondrias, endoplasmic reticulum. Blood triglycerides and apo B are rather low. After six weeks of colchicine treatment, needle biopsy shows no more active congestion nor erythrodiapedesis. Triglyceride storage lowers to 40 per cent. After seven months of colchicine treatment, triglyceride storage falls down to 12 per cent. FMF may be considered as a cause of fatty liver when there is not any cause else and only after deep decrease or disparition of triglyceride deposit by a long time colchicine treatment.
The state of the tactile cells (Merkel's cells) in epithelium of the internal follicle in the cat sinuous hairs is controlled by sensitive neurons. This statement, derived from the experiments on denervation, was analysed in the investigation when colchicine (an agent blocking axoplasmic transport) was applied on the nerve. Thirty and 60 days after colchicine effect a statistically important decrease in the number of the tactile cells with certain changes in their structure (cytoplasmic consolidation, changes in density of specific granules, increasing number and size of vacuoles) was registered. In epithelium of the internal hairy follicle a contact of the tactile cells with tactile menisci was followed. As in myelin neural fibres of the internal hairy follicle connective tissue, certain signs of destruction, resulting from blockade of colchicine-induced axoplasmic transport, were noted. Participation of the axoplasmic transport in the neurosensory control for the state of the tactile cells is discussed together with the changes described.
A rapid and convenient radioligand assay was used to characterise the interaction of several structurally diverse microtubule inhibitors with the colchicine binding domain of tubulin. Values determined for the inhibition of [3H]mebendazole binding to tubulin by colchicine, combretastatin A4, NSC 181928, NSC 321567, podophyllotoxin and tubulozole-C provided an independent measure of the relative potency of these compounds. This methodology has several advantages over the inhibition of [3H]colchicine binding as a technique for investigating the molecular mechanisms involved in determining tubulin-ligand interactions.
The effect of alcoholic solutions with 20% podophyllin from Podophyllum peltatum and Podophyllum emodi, 8% podophyllotoxin, and 8% colchicine, when applied to penile condylomata acuminata in 227 men, were statistically alike. Of the patients initially judged to be cured after 1-2 applications, 13% showed recurrence, thus bringing down the permanent cure frequency to only 43%. Local side effects were absent after only half the series of colchicine applications, whereas as much as about 3/4 of the treatment course with podophyllin and pure podophyllotoxin could be completed without provoking discomfort. Warts in the urinary meatus healed significantly less well than warts on the other genital mucous membranes. Eighty-nine per cent of patients who had previously been cured of concylomata became wart-free after 1-2 treatments, as opposed to only 40% of those who had never had this wart type previously. The use of the commercially available colchicine offers an opportunity to establish a standardized therapy; following application of an 8% solution, rinsing off should be performed after 6-8 hours.
Familial Mediterranean fever (FMF) is a genetic disorder virtually restricted to people originating from the Middle East. It is characterized by short, self-limiting, febrile attacks of peritonitis, synovitis, pleuritis or an erysipelas-like erythema. Without treatment systemic amyloidosis often develops and causes death in renal failure, usually at an early age. Two siblings with FMF and renal amyloidosis are presented. One had nephrotic syndrome, the other severe proteinuria. Continuous colchicine treatment reverse the nephrotic syndrome and in both patients the proteinuria was reduced. It is concluded, that even though colchicine can improve severe renal amyloidosis, early diagnosis of FMF is crucial because continuous colchicine treatment prevents both the febrile attacks and the amyloidosis.
IL-1 beta is a proinflammatory cytokine secreted chiefly by monocytes and macrophages. Currently, much of its mechanism of processing and secretion is poorly understood, but there is increasing evidence that the microtubule system may be involved. For example, it is known that taxol and colchicine, two drugs that affect microtubule structure and function, increase LPS-induced IL-1 beta release. However, it is not known whether these drugs affect the synthesis of the 31-kDa precursor (pro-IL-1 beta) or the processing and release of mature IL-1 beta. To test this, an assay was used that allowed for the temporal separation of IL-1 beta synthesis and release. The addition of taxol or colchicine to the secretory phase of the assay resulted in no significant change in IL-1 beta release. However, when these drugs were added to the stimulus for IL-1 beta production, there was a significant increase in both IL-1 beta release and total IL-1 beta production, as measured by ELISA. These findings indicate that taxol and colchicine increase LPS-induced IL-1 beta release by an increase in the production of the precursor molecule. Thus, it is unlikely that microtubules are involved in the IL-1 beta secretory machinery in any significant manner, but they do play a role in the regulation of pro-IL-1 beta production.
The presented case concerns a 77-year old man who had been chronically taking colchicine for treatment of gout. He was admitted because of a transient ischemic cerebrovascular attack with motor aphasia and complained of preexisting paraesthesias in the lower extremities. Neurological examination revealed a global muscular weakness, absent myotatic reflexes and a diminished sensation. Serum creatine kinase (CK) levels were increased and electromyography showed spontaneous fibrillations in deltoid muscles, positive spikewaves in deltoids and anterior tibial muscles. Motor and sensory conduction velocities were mildly reduced. Nerve biopsy findings were compatible with a chronic axonal neuropathy having produced a significant loss of myelinated axons and also denervation features of unmyelinated axons. In muscle, combined neurogenic and myogenic features were found. The former result from the axonal neuropathy. The latter were mainly characterized by focal myofibrillar disorganisation and accumulation of autophagic vacuoles in muscle fibres. The presented neuromuscular symptoms and signs, the increased CK values, the electromyographic and nerve conduction velocity findings as well as nerve and muscle biopsy observations, are consistent with the diagnosis of colchicine-induced myopathy and neuropathy. Furthermore, the disappearance of paraesthesias, normalisation of CK values, and disappearance of fibrillations and positive spike waves in deltoid and anterior tibial muscles on electromyography, after stopping of the colchicine therapy, supported the diagnosis.
With the aim of revealing endonuclease(s), activating in apoptotic cells, a nuclease activity of nuclear protein extract from human leukemic HL-60 cells treated with colchicine was studied. After a 30 h incubation with colchicine, a specific DNA fragmentation--a multiple of 200 base pair subunits--was clearly observed that was an evidence for the endonuclease activation. After 48 h almost the whole DNA was fragmented. At the same time histones appeared the major proteins of nuclear extract. Using the method for detection of nuclease activity in a gel, protein 37 kDa was identified as a Ca2+, Mg(2+)-dependent endonuclease. The maximum increase in nuclease activity occurred after a 24 h incubation with colchicine. A low activity of this protein was also found in control cells. These data suggest that in apoptotic cells activation of constantly expressed nucleases may occur, rather than a new synthesis of apoptotic nucleases.
Laminated pacinian corpuscles from the cat mesentery have been studied morphologically and morphometrically after nerve section and colchicine application to the nerve and the results obtained are represented. Similar interventions in the nerve produce changes in the receptors resembling those of wallerian type degeneration, degeneration rate after sectioning being higher than after colchicine application. At early stages after colchicine application the internal cone and its nuclei increase in size. The data obtained suggest the nuclei of the internal cone to be under neurotrophic control of the sensory neuron that might be realized via axoplasmic transport of substances.
A 45-year-old male was admitted to hospital after 2 to 3 days of vomiting, nausea, and diarrhea following an apparent overdose of colchicine tables. During hospitalization his white blood cell count fell dramatically. At death, 33 h following initial hospitalization, pleural effusion with bilateral bronchopneumonia was evident, together with numerous bacterial colonies and marked hypocellularity of bone marrow and reduced megakaryocytes, erythroid, and myeloid cells. The most striking histological findings were numerous metaphasic mitotic figures in gastric and small bowel epithelia. Colchicine was detected, confirmed by high pressure liquid chromatography with photodiode array detection, and quantitated in antemortem plasma collected 3.3 h following hospitalization and in postmortem blood and bile. Colchicine was not detected in liver, vitreous humor, or stomach contents.
A colchicine-like substance, vincaleukoblastine (2.10-4M, 3 to 6 hours), prevents the blocking of the centrosphere which would be produced by quinoline or by a similar substance (glutaraldehyde), to the extent of the inhibition of polarity by this colchicine-like substance. This is interpreted as due to the fact that each molecule of colchicine-like substance binds to a single subunit (or heterodimer) of tubulin and consequently prevents the constitution of storage structures. It is supposed that on the contrary quinoline-like substances bind to several subunits of tubulin and that they can stabilize the storage structures, binding to them in several points. The ultrastructural study demonstrates that when the centrosphere is blocked by quinoline, there is accumulation, hypertrophy and permanence of the "dense bodies" later than prophase; sometimes they are fused in a large "dense mass". The "dense bodies", and perhaps the "striated bodies", may therefore be interpreted as constituting morphologically the storage structures, which enlarge when all the astral and spindle microtubules completely disappear by action of a quinoline-like substance.