Review

Authors: Spyridon G Deftereos, Frans J Beerkens, Binita Shah...

Inflammation plays a prominent role in the development of atherosclerosis and other cardiovascular diseases, and anti-inflammatory agents may improve cardiovascular outcomes. For years, colchicine has been used as a safe and well-tolerated agent in diseases such as gout and familial Mediterranean fever. The widely available therapeutic has several anti-inflammatory effects, however, that have proven effective in a broad spectrum of cardiovascular diseases as well. It is considered standard-of-care therapy for pericarditis, and several clinical trials have evaluated its role in postoperative and postablation atrial fibrillation, postpericardiotomy syndrome, coronary artery disease, percutaneous coronary interventions, and cerebrovascular disease. We aim to summarize colchicine's pharmacodynamics and the mechanism behind its anti-inflammatory effect, outline thus far accumulated evidence on treatment with colchicine in cardiovascular disease, and present ongoing randomized clinical trials. We also emphasize real-world clinical implications that should be considered on the basis of the merits and limitations of completed trials. Altogether, colchicine's simplicity, low cost, and effectiveness may provide an important addition to other standard cardiovascular therapies. Ongoing studies will address complementary questions pertaining to the use of low-dose colchicine for the treatment of cardiovascular disease.

Topics: Cardiovascular Diseases; Colchicine; Gout Suppressants; Humans

PubMed: 34965168
DOI: 10.1161/CIRCULATIONAHA.121.056171

Review

Authors: Massimo Imazio, Mark Nidorf

Colchicine is a unique, sophisticated anti-inflammatory agent that has been used for decades for the prevention of acute inflammatory flares in gout and familial Mediterranean fever. In recent years, clinical trials have demonstrated its potential in a range of cardiovascular (CV) conditions. Colchicine is avidly taken up by leucocytes, and its ability to bind to tubulin and interfere with microtubular function affects the expression of cytokines and interleukins, and the ability of neutrophils to marginate, ingress, aggregate, express superoxide, release neutrophil extracellular traps, and interact with platelets. In patients with acute and recurrent pericarditis, clinical trials in >1600 patients have consistently shown that colchicine halves the risk of recurrence [relative risk (RR) 0.50, 95% confidence interval (CI) 0.42-0.60]. In patients with acute and chronic coronary syndromes, multicentre randomized controlled trials in >11 000 patients followed for up to 5 years demonstrated that colchicine may reduce the risk of CV death, myocardial infarction, ischaemic stroke and ischaemia-driven revascularization by >30% (RR 0.63, 95% CI 0.49-0.81). The use of colchicine at doses of 0.5-1.0 mg daily in CV trials has proved safe. Early gastrointestinal intolerance limits its use in ∼10% of patients; however, ∼90% of patients tolerate it well over the long term. Despite isolated case reports, clinically relevant drug interactions with moderate to strong CYP3A4 inhibitors/competitors or P-glycoprotein inhibitors/competitors are rare if this dosage of colchicine is used in the absence of advanced renal or liver disease. The aim of this review is to summarize the contemporary data supporting the efficacy and safety of colchicine in patients with CV disease.

Topics: Anti-Inflammatory Agents; Brain Ischemia; Colchicine; Humans; Pericarditis; Stroke

PubMed: 33961006
DOI: 10.1093/eurheartj/ehab221

Review

Authors: Nicola Dalbeth, Thomas J Lauterio, Henry R Wolfe...

PURPOSE

The aims of this article were to systematically review the literature about the mechanism of action of colchicine in the multimodal pathology of acute inflammation associated with gout and to consider the clinical utility of colchicine in other chronic inflammatory diseases.

METHODS

The English-language literature on PubMed was searched for articles published between 1990 and October 2013, with a cross-reference to citations across all years. Relevant articles pertaining to the mechanism of action of colchicine and the clinical applications of colchicine in gout and other inflammatory conditions were identified and reviewed.

FINDINGS

The molecular pathology of acute inflammation associated with gouty arthritis involves several concurrent pathways triggered by a variety of interactions between monosodium urate crystals and the surface of cells. Colchicine modulates multiple pro- and antiinflammatory pathways associated with gouty arthritis. Colchicine prevents microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis. Many of these cellular processes can be found in other diseases involving chronic inflammation. The multimodal mechanism of action of colchicine suggests potential efficacy of colchicine in other comorbid conditions associated with gout, such as osteoarthritis and cardiovascular disease.

IMPLICATIONS

Colchicine has multiple mechanisms of action that affect inflammatory processes and result in its utility for treating and preventing acute gout flare. Other chronic inflammatory diseases that invoke these molecular pathways may represent new therapeutic applications for colchicine.

Topics: Animals; Anti-Inflammatory Agents; Chronic Disease; Colchicine; Gout; Gout Suppressants; Humans

PubMed: 25151572
DOI: 10.1016/j.clinthera.2014.07.017

Review

Authors: Ying Ying Leung, Laura Li Yao Hui, Virginia B Kraus...

OBJECTIVES

To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions.

METHODS

We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed.

RESULTS

The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis.

CONCLUSION

Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions.

Topics: Arthritis, Gouty; Colchicine; Gout; Gout Suppressants; Humans; Tubulin

PubMed: 26228647
DOI: 10.1016/j.semarthrit.2015.06.013

Review

Authors: Leo F Buckley, Peter Libby

Colchicine-an anti-inflammatory alkaloid-has assumed an important role in the management of cardiovascular inflammation ≈3500 years after its first medicinal use in ancient Egypt. Primarily used in high doses for the treatment of acute gout flares during the 20th century, research in the early 21st century demonstrated that low-dose colchicine effectively treats acute gout attacks, lowers the risk of recurrent pericarditis, and can add to secondary prevention of major adverse cardiovascular events. As the first Food and Drug Administration-approved targeted anti-inflammatory cardiovascular therapy, colchicine currently has a unique role in the management of atherosclerotic cardiovascular disease. The safe use of colchicine requires careful monitoring for drug-drug interactions, changes in kidney and liver function, and counseling regarding gastrointestinal upset. Future research should elucidate the mechanisms of anti-inflammatory effects of colchicine relevant to atherosclerosis, the potential role of colchicine in primary prevention, in other cardiometabolic conditions, colchicine's safety in cardiovascular patients, and opportunities for individualizing colchicine therapy using clinical and molecular diagnostics.

Topics: Humans; Anti-Inflammatory Agents; Cardiovascular Diseases; Colchicine; Drug Interactions; Gout Suppressants; Treatment Outcome

PubMed: 38511324
DOI: 10.1161/ATVBAHA.124.319851

Authors: Ryan S Nett, Warren Lau, Elizabeth S Sattely...

Few complete pathways have been established for the biosynthesis of medicinal compounds from plants. Accordingly, many plant-derived therapeutics are isolated directly from medicinal plants or plant cell culture. A lead example is colchicine, a US Food and Drug Administration (FDA)-approved treatment for inflammatory disorders that is sourced from Colchicum and Gloriosa species. Here we use a combination of transcriptomics, metabolic logic and pathway reconstitution to elucidate a near-complete biosynthetic pathway to colchicine without prior knowledge of biosynthetic genes, a sequenced genome or genetic tools in the native host. We uncovered eight genes from Gloriosa superba for the biosynthesis of N-formyldemecolcine, a colchicine precursor that contains the characteristic tropolone ring and pharmacophore of colchicine. Notably, we identified a non-canonical cytochrome P450 that catalyses the remarkable ring expansion reaction that is required to produce the distinct carbon scaffold of colchicine. We further used the newly identified genes to engineer a biosynthetic pathway (comprising 16 enzymes in total) to N-formyldemecolcine in Nicotiana benthamiana starting from the amino acids phenylalanine and tyrosine. This study establishes a metabolic route to tropolone-containing colchicine alkaloids and provides insights into the unique chemistry that plants use to generate complex, bioactive metabolites from simple amino acids.

Topics: Biosynthetic Pathways; Colchicaceae; Colchicine; Cytochrome P-450 Enzyme System; Gene Expression Regulation, Plant; Metabolic Engineering; Metabolomics; Phenylalanine; Nicotiana; Transcriptome; Tyrosine

PubMed: 32699417
DOI: 10.1038/s41586-020-2546-8

Review

Authors: John Stack, Geraldine McCarthy

In contrast to gout, no disease-modifying therapies currently exist that reduce articular crystal deposition of calcium pyrophosphate crystals (CPPs). Treatment is aimed at ameliorating the inflammatory response and reducing the frequency and severity of clinical symptoms due to CPP deposition (CPPD). Despite being one of the most common forms of inflammatory arthritis, CPPD remains under-studied and evidence-based treatment guidelines remain lacking. Commonly used treatments for clinical manifestations of CPPD (non-steroidal anti-inflammatory drugs [NSAIDs], colchicine and corticosteroids [CSs]) are extrapolated from use in gout. Anakinra and tocilizumab can be used in refractory cases. Though no current crystal-targeted treatments exist, studies suggest that nucleoside analogues and phosphocitrate can attenuate calcification of human cartilage ex-vivo. Hindering research, is the lack of a well-defined description of CPPD. However, international working groups have convened to establish classification criteria and validated outcome domains for CPPD. This should help facilitate the setting up of large multicentre studies, with well-defined cohorts, which can evaluate suitable therapies, providing high levels of evidence to guide clinicians. Here, we summarise and discuss the currently available anti-inflammatory treatment options for CPPD and discuss potential future crystal-targeted approaches.

Topics: Calcium Pyrophosphate; Chondrocalcinosis; Colchicine; Gout; Humans; Joints

PubMed: 34756508
DOI: 10.1016/j.berh.2021.101720

Randomized Controlled Trial

Authors: Jiejie Li, Xia Meng, Fu-Dong Shi...

OBJECTIVES

To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3).

DESIGN

Multicentre, double blind, randomised, placebo controlled trial.

SETTING

244 hospitals in China between 11 August 2022 and 13 April 2023.

PARTICIPANTS

8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled.

INTERVENTIONS

Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days.

MAIN OUTCOME MEASURES

The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat.

RESULTS

4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83).

CONCLUSIONS

The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L.

TRIAL REGISTRATION

ClinicalTrials.gov, NCT05439356.

Topics: Humans; Colchicine; Male; Female; Double-Blind Method; Middle Aged; Ischemic Attack, Transient; Aged; Ischemic Stroke; Treatment Outcome; China; C-Reactive Protein; Adult

PubMed: 38925803
DOI: 10.1136/bmj-2023-079061

Review

Authors: Fan-Shun Zhang, Qing-Ze He, Chengxue Helena Qin...

Colchicine is an ancient herbal drug derived from Colchicum autumnale. It was first used to treat familial Mediterranean fever and gout. Based on its unique efficacy as an anti-inflammatory agent, colchicine has been used in the therapy of cardiovascular diseases including coronary artery disease, atherosclerosis, recurrent pericarditis, vascular restenosis, heart failure, and myocardial infarction. More recently, colchicine has also shown therapeutic efficacy in alleviating cardiovascular complications of COVID-19. COLCOT and LoDoCo2 are two milestone clinical trials that confirm the curative effect of long-term administration of colchicine in reducing the incidence of cardiovascular events in patients with coronary artery disease. There is growing interest in studying the anti-inflammatory mechanisms of colchicine. The anti-inflammatory action of colchicine is mediated mainly through inhibiting the assembly of microtubules. At the cellular level, colchicine inhibits the following: (1) endothelial cell dysfunction and inflammation; (2) smooth muscle cell proliferation and migration; (3) macrophage chemotaxis, migration, and adhesion; (4) platelet activation. At the molecular level, colchicine reduces proinflammatory cytokine release and inhibits NF-κB signaling and NLRP3 inflammasome activation. In this review, we summarize the current clinical trials with proven curative effect of colchicine in treating cardiovascular diseases. We also systematically discuss the mechanisms of colchicine action in cardiovascular therapeutics. Altogether, colchicine, a bioactive constituent from an ancient medicinal herb, exerts unique anti-inflammatory effects and prominent cardiovascular actions, and will charter a new page in cardiovascular medicine.

Topics: Anti-Inflammatory Agents; Cardiovascular Agents; Colchicine; Coronary Artery Disease; Humans; Myocardial Infarction; COVID-19 Drug Treatment

PubMed: 35046517
DOI: 10.1038/s41401-021-00835-w

Authors: Peter M Andel, Pål Aukrust, Jostein Gleditsch...

Pericarditis is an important differential diagnosis in patients with chest pain. The two most common causes in the developed world are idiopathic pericarditis and inflammation following cardiac surgery or myocardial infarction. Recurrence of pericarditis affects up to 30 % of patients, half of whom experience multiple episodes, and approximately 10 % develop steroid-dependent and colchicine-refractory pericarditis. Recurrence is due to autoinflammatory processes in the pericardium. Advanced diagnostic imaging and treatment with colchicine and interleukin-1 inhibitors has helped reduce morbidity considerably in recent years. In this clinical review, we summarise up-to-date knowledge about the diagnostic evaluation and treatment of patients with recurrent primary pericarditis.

Topics: Humans; Pericarditis; Colchicine; Myocardial Infarction; Inflammation; Recurrence

PubMed: 37254974
DOI: 10.4045/tidsskr.22.0580