ReviewColchicine: Old and New
Section snippets
Pharmacologic Properties
Colchicine is a tricyclic, lipid-soluble alkaloid with a long terminal half-life (20 to 40 hours) and bioavailability ranging from 24% to 88% (Figure 1). Within the bloodstream, ∼40% of colchicine binds to albumin.26 Although peak plasma concentrations occur 1 hour after administration, maximal anti-inflammatory effects develop over 24 to 48 hours, based on intraleukocyte accumulation.27 Colchicine reaches much higher concentrations within leukocytes than in plasma, and persists there for
Mechanisms of Action
Colchicine binds to free tubulin dimers, which, when incorporated into nascent microtubules, disrupt further microtubule polymerization. Abrogation of microtubule polymerization inhibits vesicle transport, cytokine secretion, phagocytosis, migration, and division. At higher concentrations, colchicine may also induce some microtubule dissociation.39
In neutrophils, colchicine inhibits intracellular signaling molecules including tyrosine kinases and phospholipases, and inhibits chemotaxis and
Colchicine Toxicity
The commonest side effects of colchicine are gastrointestinal, with nausea, vomiting, and particularly diarrhea occurring in 5%-10% of patients, even at recommended doses. Dose reduction may permit resolution of these symptoms. Colchicine doses of 0.5 to 0.8 mg/kg are highly toxic, and doses of more than 0.8 mg/kg are typically lethal; to reduce the risk of irreversible bolus overdose, the FDA withdrew approval for intravenous colchicine.40, 48 Acute overdose usually manifests as
Gout and Calcium Pyrophosphate Crystal Arthritis
Many of the inflammatory processes discussed above are relevant to gout pathogenesis. Gouty inflammation relies on the activation of macrophages and neutrophils, depends upon the expression of adhesion molecules on leukocytes and vasculature, and is triggered by crystal-induced inflammasome activation and IL-1β generation, all of which can be abrogated by colchicine (Figure 3).58, 59, 60, 61, 62
Although colchicine has been used to treat gout for centuries, relatively few controlled trials have
Colchicine and Cardiovascular Disease
The accumulating understanding of the role of inflammation in cardiovascular diseases has been accompanied by recognition of the possible anti-inflammatory benefit of colchicine in these settings.
Conclusion
Colchicine is one of the oldest therapeutic substances known to mankind, yet the scope of its benefits has only recently been the subject of active study. Because of its wide range of activities among inflammatory cells, its systemic effect and its relatively mild side-effect profile at recommended doses, colchicine has proved to be beneficial in some common and frustrating conditions, including some forms of cardiovascular disease. Ongoing research will further elucidate the mechanisms of
Acknowledgment
Support: MHP is supported in part by CTSA grant UL1TR000038 from the National Center for the Advancement of Translational Science, National Institutes of Health. SK is supported in part by a New York State Empire Clinical Research Investigator Program Award.
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Funding: None.
Conflict of Interest: AS: None. SK: None. MHP is the recipient of an investigator-initiated grant and also serves as a study site investigator for a trial supported by Takeda, Inc.; is the recipient of an investigator-initiated grant from Savient, Inc.; is the recipient of an investigator-initiated grant and has served as a consultant for Crealta, Inc.; and has served as a consultant for Astra-Zeneca, Inc. BS is the recipient of an investigator-initiated grant (drug and placebo only) from Takeda, Inc.
Authorship: All authors participated in all aspects of this manuscript, including conception, research, writing, and editing.