Colchicine

doi:10.1016/0049-0172(74)90006-7

Seminars in Arthritis and Rheumatism

Volume 3, Issue 4, Summer 1974, Pages 369-381

https://doi.org/10.1016/0049-0172(74)90006-7 Get rights and content

Abstract

The clinical pharmacology of colchicine has been reviewed and its therapeutic use described. There is still some disagreement about its diagnostic utility; it is clearly most effective in acute gout, but benefit has been reported from its use in sarcoid arthritis and in the inflammation associated with hydroxyapatite deposition.

Colchicine toxicity is largely gastrointestinal in customary doses, with a choleriform syndrome of varying severity produced in 80% of patients. Larger doses in addition produce disseminated intravascular coagulation, marrow failure, hepatocellular failure, and late central-nervous-system dysfunction, among other effects. Treatment of colchicine toxicity is supportive.

Colchicine metabolic studies demonstrate that the drug leaves the blood rapidly and remains in cells for protracted periods of time. Measurable amounts were still found in leukocytes as late as 10 days after a single administration, and urinary excretion persisted for a similar length of time.

A comparison of the relation between function and the structure of colchicine and its analogues in the human and in two species of rodent revealed significant variability in results. It was concluded that urate crystal-induced inflammation in the rodent was not necessarily a suitable model for human acute gout.

Studies of colchicine's mechanism of action in acute gout have previously suggested that it depended on interference with microtubular subunit protein aggregation. Evidence is here summarized that colchicine may have other effects on the cell and that the benefit in gout may possibly be unrelated to the microtubular action.

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Colchicine-intolerant familial mediterranean fever patients: A comparative study between different colchicine doses and IL-1 inhibitor monotherapy
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Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease. Colchicine is the primary treatment for FMF, although some patients do not respond well or are unable to tolerate it. For these patients, the addition of interleukin-1 (IL-1) antagonists is the preferred option. However, the impact of colchicine treatment alongside the use of IL-1 antagonists remains unclear.
We recruited adult FMF patients who satisfied the Eurofever and Pediatric Rheumatology International Trials Organization classification criteria and were receiving IL-1 antagonist treatment from our FMF cohort. All the patients exhibited colchicine intolerance or resistance. As per the FMF cohort protocol, the patients were longitudinally followed up, including assessments of their C-reactive protein, erythrocyte sedimentation rate, autoinflammatory disease activity index (AIDAI), and autoinflammatory damage index (ADDI).
Among the 125 patients (68 female and 57 male), 96 received a combination of IL-1 antagonists and the maximum tolerated dose of colchicine, whereas 29 were treated exclusively with IL-1 antagonists due to colchicine intolerance. The patients’ inflammatory markers, AIDAI activity, and ADDI damage scores did not differ significantly between the two groups during the follow-up period. Notably, the drug retention rates were significantly higher in the patients treated solely with IL-1 antagonists.
While the typical approach is to maintain colchicine treatment alongside the use of IL-1 antagonists, for patients who cannot tolerate effective colchicine doses, IL-1 antagonists alone may effectively control FMF disease activity.
Synthesis, anticancer activity and molecular docking studies of N-deacetylthiocolchicine and 4-iodo-N-deacetylthiocolchicine derivatives
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Citation Excerpt :
13C NMR (101 MHz, CDCl3) δ 182.4, 173.6, 158.1, 153.5, 151.6, 151.1, 141.6, 138.4, 134.6, 134.4, 128.4, 126.6, 125.7, 107.3, 61.7, 61.3, 56.1, 51.9, 36.6, 29.9, 29.2, 15.1, 9.5 ppm. FT-IR: 3303, 2937, 1660, 1607, 1543, 1486, 1462, 1425, 1404, 1349, 1321, 1283, 1235, 1196, 1154, 1138, 1096, 1022 cm−1. ESI-MS (m/z): [M+H]+ calcd 430, found 430, [M+Na]+ calcd 552, found 552 [M+K]+ calcd 468, found 468.
Colchicine is a plant alkaloid with a broad spectrum of biological and pharmacological properties. It has found application as an anti-inflammatory agent and also shows anticancer effects through its ability to destabilize microtubules by preventing tubulin dimers from polymerizing leading to mitotic death. However, adverse side effects have so far restricted its use in cancer therapy. This has led to renewed efforts to identify less toxic derivatives. In this article, we describe the synthesis of a set of novel double- and triple-modified colchicine derivatives. These derivatives were tested against primary acute lymphoblastic leukemia (ALL-5) cells and several established cancer cell lines including A549, MCF-7, LoVo and LoVo/DX. The novel derivatives were active in the low nanomolar range, with 7-deacetyl-10-thiocolchicine analogues more potent towards ALL-5 cells while 4-iodo-7-deacetyl-10-thiocolchicine analogues slightly more effective towards the LoVo cell line. Moreover, most of the synthesized compounds showed a favorable selectivity index (SI), particularly for ALL-5 and LoVo cell lines. Cell cycle analysis of the most potent molecules on ALL-5 and MCF-7 cell lines revealed contrasting effects, where M-phase arrest was observed in MCF-7 cells but not in ALL-5 cells. Molecular docking studies of all derivatives to the colchicine-binding site were performed and it was found that five of the derivatives showed strong β-tubulin binding energies, lower than −8.70 kcal/mol, while the binding energy calculated for colchicine is −8.09 kcal/mol. The present results indicate that 7-deacetyl-10-thiocolchicine and 4-iodo-7-deacetyl-10-thiocolchicine analogues constitute promising lead compounds as chemotherapy agents against several types of cancer.
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Colchicine (1) is a plant alkaloid isolated from Colchicum autumnale [1].
Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC₅₀ values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different β tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.
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Repeat complete blood cell counts are recommended, owing to the possibility of bone marrow suppression.13 Severe local irritation subsequent to extravasation and thrombophlebitis has been observed if colchicine is administered intravenously.25 It has been reported that colchicine may cause nausea, vomiting, and diarrhea in dogs.13,27
Comparative effect of colchicine and colchiceine on cytotoxicity and CYP gene expression in primary human hepatocytes
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The aims of the present study were (1) to determine the cytotoxicity of colchiceine (EIN) in comparison with that of colchicine (COL); (2) to evaluate the effect of EIN on cytochrome P450 (CYP) expression and activity. Primary human hepatocytes were the model of choice for cytotoxicity and CYP expression experiments. LDH leakage and albumin secretion served as cytotoxicity parameters. EIN was less toxic than COL based on both parameters within the concentration range 1–100 μm. 10 μm concentration of EIN did not induce the expression of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 isoforms, which were evaluated at the levels of mRNAs, proteins and specific activities in culture. EIN in concentrations up to 200 μm had no effect on marker activities of CYP1A2, 2C9, 2E1 and 3A4 in human liver microsomes. It was concluded that EIN in concentrations up to 10 μm is not cytotoxic in primary human hepatocytes as revealed by albumin secretion and LDH leakage. Possible drug–drug interactions of EIN due to effects on cytochromes P4501A2, 2C9, 2E1 and 3A4 isoforms are unlikely because inhibition/induction studies show any lack of such effects. As EIN was shown to have better antifibrotic properties than COL (European Journal of Clinical Investigation 1997, 2, 77), it can be used as a COL substitute with anticipated fewer side-effects.

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¹: From the Department of Medicine, Jewish Hospital and Medical Center of Brooklyn, Brooklyn, N.Y., and the Department of Medicine, New York University-Bellevue Medical Center, New York, N.Y.

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Colchicine

Abstract

Am J Med

J Clin Nutrition

Am J Med

Fertil Steril

Am J Obstet Gynecol

Biochem Med

Metabolism

Lancet

Exp Cell Res

Biochem Pharmacol

A wit and his gout: The Reverend Sydney Smith

Arthritis Rheum

The early history of anti-rheumatic drugs

Arthritis Rheum

Colchicum: The panacea

Bull NY Acad Med

The treatment of gout

Arthritis Rheum

Diagnostic value of the colchicine therapeutic trial

JAMA

Efficacy of colchicine prophylaxis in gout

Ann Intern Med

Diagnosis of gout

Clin Orthop

Goals in gout

Postgrad Med

A discussion of a therapeutic test and a provocative test in gouty arthritis

Ann Intern Med

Test of non-specific anti-inflammatory activity of colchicine

Arthritis Rheum

Response to colchicine therapeutic trial in rheumatoid arthritis

N Engl J Med

Sarcoid arthritis with a response to colchicine

N Engl J Med

Further experiences with colchicine in the treatment of sarcoid arthritis

N Engl J Med

The syndrome of sarcoidosis, psoriasis and gout

Ann Intern Med

Significance of urate crystals in synovial fluids

Arch Intern Med

Treatment with colchicine of the periarticular inflammation associated with sarcoidosis: A need for continued appraisal

Arthritis Rheum

Recurrent acute inflammation associated with focal apatite crystal deposition

Arthritis Rheum

Calcific tendinitis and soft-tissue calcification resembling gout

JAMA

Gout and pseudogout

Geriatrics

Colchicine: Anti-inflammatory effects of low doses in a sensitive bacterial system

J Lab Clin Med

Colchicine for familial Mediterranean fever

N Engl J Med

Colchicine for familial Mediterranean fever

N Engl J Med

Colchicine for familial Mediterranean fever

N Engl J Med

Colchicine for familial Mediterranean fever

N Engl J Med

The arthritis of familial Mediterranean fever

Arthritis Rheum

Colchicine for familial Mediterranean fever

N Engl J Med

Intestinal malabsorption induced by oral Colchicine

Am J Med Sci

Mechanism of vitamin B12 malabsorption in patients receiving colchicine

N Engl J Med

Colchicine intoxication

Hum Pathol

Donnees actuelles sur l'intoxication aigue par la colchicine

Ann Med Interne

Bone marrow depression associated with acute colchicine toxicity in the presence of hepatic dysfunction

Cancer

Etude de l'hemostase au cours des intoxications aigues par la colchicine

Eur J Toxicol

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Mechanism of vitamin B₁₂ malabsorption in patients receiving colchicine