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Colchicine anti-inflammatory actions start with the interference with microtubule assembly and function and its capability to concentrate in inflammatory cells with limited expression of P-glycoprotein (e.g. granulocytes). Anti-inflammatory effects of colchicine are derived from a combination of different actions: (i) inhibition of granulocytes, (ii) interference with qualitative and quantitative expression of selectins on endothelial and inflammatory cells and platelet aggregation stimulated by inflammation, and (iii) non-specific inhibition of the inflammasome by interference with the assembly of its components when inflammation is stimulated.
Source publication
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 abi...
Context in source publication
Context 1
... binds to tubulin heterodimers and alters the tubulin conformation, preventing any further growth of microtubules at low doses, but promoting their depolymerisation at high doses. 3 Anti-inflammatory effects of colchicine are derived from a combination of actions ( Figure 2). The effect of colchicine on tubulin affects the assembly of inflammasome and the expression of interleukin (IL)-1b, and other ILs, including IL-18 by macrophages; and impairs neutrophil chemotaxis, adhesion, mobilization, recruitment, production and release of superoxide, and the expression of neutrophil extracellular traps (NETs). ...
Citations
... Its wide availability, low cost and considerable safety profile have motivated investigations into its application against cardiovascular diseases by targeting the inflammatory axis (Deftereos et al., 2022). Colchicine has broad anti-inflammatory effects and functions by binding to tubulin, inhibiting tubulin polymerisation and the assembly of the inflammasome (Deftereos et al., 2022;Imazio & Nidorf, 2021). Further, it disrupts the cellular cytoskeleton, mitosis and intracellular transport and inhibits the migration of neutrophils to inflamed regions (chemotaxis) (Deftereos et al., 2022). ...
Inflammatory signalling via the nod‐like receptor (NLR) family pyrin domain‐containing protein‐3 (NLRP3) inflammasome has recently been implicated in the pathophysiology of atrial fibrillation (AF). However, the precise role of the NLRP3 inflammasome in various cardiac cell types is poorly understood. Targeting components or products of the inflammasome and preventing their proinflammatory consequences may constitute novel therapeutic treatment strategies for AF. In this review, we summarise the current understanding of the role of the inflammasome in AF pathogenesis. We first review the NLRP3 inflammasome pathway and inflammatory signalling in cardiomyocytes, (myo)fibroblasts and immune cells, such as neutrophils, macrophages and monocytes. Because numerous compounds targeting NLRP3 signalling are currently in preclinical development, or undergoing clinical evaluation for other indications than AF, we subsequently review known therapeutics, such as colchicine and canakinumab, targeting the NLRP3 inflammasome and evaluate their potential for treating AF.
... Colchicine interferes with microtubule assembly, resulting in inhibition of the inflammasome activation which is required for proinflammatory cytokine expression. 41 Colchicine also inhibits neutrophil function, adhesion molecule expression, and interferes neutrophil-platelet aggregation. 41 Clinical studies have shown that colchicine reduced MACE, but no significant reduction in ischemic stroke was observed in subgroup analysis. ...
... 41 Colchicine also inhibits neutrophil function, adhesion molecule expression, and interferes neutrophil-platelet aggregation. 41 Clinical studies have shown that colchicine reduced MACE, but no significant reduction in ischemic stroke was observed in subgroup analysis. 42 Several clinical trials on colchicine in stroke prevention are still underway, 43 including one targeting arterial inflammation in patients with diabetes (NCT04181996). ...
Stroke is the leading cause of disability and the second leading cause of death worldwide. Diabetes mellitus is a critical independent cardiovascular risk factor in patients, irrespective of age, smoking, and hypertension. Approximately one-third of first-time ischemic stroke patients have diabetes. Inflammation is among the most important pathological mechanisms in atheroma formation, the damage cascades of the acute phase, as well as during the subacute and chronic phases after stroke. Diabetes, as a common risk factor for stroke, is often present for a long time before a stroke occurs, causing low-grade inflammation, and disrupting the proper functioning of the neurovascular units. These proinflammatory processes and maladaptive immune mechanisms are further accelerated after cerebral ischemia and worsen the stroke outcome in diabetic patients. Clinical treatments for ischemic stroke are currently focused on restoring cerebral blood flow (reperfusion) in the acute phase, including thrombolysis and mechanical thrombectomy, which are not applicable to patients that fall outside of the treatment window and/or without large-vessel occlusion. There are few approved treatments targeting cellular injury caused by inflammation. There are even fewer data on effective treatment for diabetic stroke targeting inflammation. This paper presents the first part of a review focusing on the temporospatial aspects of inflammation in ischemic stroke pathophysiology in stroke patients with type 2 diabetes.
... produce superoxide, release neutrophil extracellular traps, and engage with platelets. 3 Data from the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) have highlighted the potential of anti-inflammatory treatments to benefit cardiovascular diseases ranging from acute coronary syndrome (ACS) and pericarditis to atrial fibrillation (AF) and secondary prevention in stable coronary artery disease (CAD). 4 More recently, the US Food and Drug Administration has approved colchicine 0.5 mg under the brand name Lodoco as an anti-inflammatory indicated for reducing cardiovascular events among adults who have established atherosclerotic cardiovascular disease. ...
Inflammation has played a pivotal role in atherosclerosis and other cardiovascular disorders, prompting the exploration of anti-inflammatory therapies to improve cardiovascular outcomes. Colchicine, a well-established agent in conditions such as gout and familial Mediterranean fever, has emerged as a promising novel anti-inflammatory agent in the realm of cardiovascular diseases. Its ability to target both traditional risk factors and residual inflammatory risk marks a significant advancement in cardiovascular prevention strategies, indicating a new era in cardiovascular care. Landmark trials have supported the efficacy and safety of low-dose colchicine in reducing major adverse cardiovascular events when combined with standard therapies. In addition, its endorsement by major cardiovascular societies underscores its significance as the first targeted anti-inflammatory therapy for cardiovascular disease. However, careful monitoring for drug interactions and adverse effects, particularly on kidney and liver function, is essential for safe use. In this review, we aim to comprehensively summarize the mechanisms of action of colchicine, its molecular and biochemical targets in various cardiovascular conditions, and its pharmacokinetics, and delve deeply into the existing evidence on its safety and efficacy in the treatment of cardiovascular disorders, including coronary artery disease, pericarditis, atrial fibrillation, and heart failure.
... Recent reports highlighted this phenomenon as a potential target for new therapies identification [9]. The inflammatory activation was found to be related not only to chronic progression [10] but also to acute cardiovascular events [11,12] and was presented as an independent potential survival modulator [13]. Zernecke et al. [14] in their analysis presented a strong atheroprotective role of innate lymphoid cells-2. ...
Background: An imbalance between pro- and anti-inflammatory mechanisms is indicated in the pathophysiology of atherosclerotic plaque. The coronary artery and carotid disease, despite sharing similar risk factors, are developed separately. The aim of this study was to analyze possible mechanisms between trace element hair–scalp concentrations and whole blood counts that favor atherosclerotic plaque progression in certain locations. Methods: There were 65 (36 (55%) males and 29 (45%) females) patients with a median age of 68 (61–73) years enrolled in a prospective, preliminary, multicenter analysis. The study group was composed of 13 patients with stable coronary artery disease (CAD group) referred for surgical revascularization due to multivessel coronary disease, 34 patients with carotid artery disease (carotid group) admitted for vascular procedure, and 18 patients in a control group (control group). Results: There was a significant difference between the CAD and carotid groups regarding lymphocyte (p = 0.004) counts. The biochemical comparison between the coronary and carotid groups revealed significant differences regarding chromium (Cr) (p = 0.002), copper (Cu) (p < 0.001), and zinc (Zn) (p < 0.001) concentrations. Spearman Rank Order Correlations between lymphocyte counts and trace elements in the analyzed groups were performed, revealing a strong correlation with zinc (R = 0.733, p < 0.001) in the control group (non-CAD, non-carotid). Conclusion: Significant differences in hair–scalp concentrations related to atherosclerosis location were observed in our analysis. The interplay between zinc concentration and lymphocyte count may play a pivotal role in cardiovascular disease development.
... In contrast, the rise in LVEDVI values in both groups at the first and third month did not meet the criteria (Table 3). Although the increase in LVESVI and LVEDVI values was lower in the colchicine group, there were no significant differences compared to the placebo group at the first (16.5% vs. 18 . Decrease of left ventricular systolic function was also observed in both groups, evidenced by a reduction in LVEF Biplane at the first and third-month evaluations (Table 3). ...
... The bioavailability of colchicine ranges from 24% to 88%, with a mean of 45%. 18 Inflammatory response after reperfusion exhibits a proinflammatory phase lasting 3 to 7 days, with the peak occurring between 24 and 72 hours. 19 An animal study found that pharmacological inhibition of the inflammasome within 1 hour of reperfusion limits secondary inflammatory injury and infarct size following myocardial ischemiareperfusion. 20 Hence, the timing of early colchicine administration in our study just before PPCI seemed appropriate. ...
Background: Inflammation in reperfusion injury results in adverse ventricular remodeling and reduced systolic function. The anti-inflammatory effects of colchicine have shown beneficial effects in cardiovascular disease. Objective: To determine the effects of low-dose colchicine on left ventricular (LV) adverse remodeling and systolic function in acute myocardial infarction with anterior ST-segment elevation (anterior STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). Material and Methods: This prospective, randomized, double-blinded study randomly assigned anterior STEMI patients who underwent PPCI to receive either low-dose colchicine (1mg loading dose followed by 0.5mg daily) or a matching placebo for 30 days in addition to standard therapy. Outcomes included adverse LV remodeling and systolic function, determined by transthoracic echocardiography (TTE) in the first and third month. Result: Enrollment comprised 196 patients, with 92 patients in the colchicine group and 104 patients in the placebo group. Adverse LV remodeling and a decrease in systolic function were observed in both groups. No significant differences in LV remodeling were observed between the colchicine and placebo groups, as indicated by the change in LV end-systolic volume index (LVESVI) at the first month (16.5% vs. 18.25% [p=0.091]) and third month (19.5% vs. 21.5% [p=0.124]). Similar results were found in LV systolic function between the colchicine and placebo groups, with a reduction in LV ejection fraction (LVEF) observed in the first month (6.3% vs. 8.95% [p=0.083]) and third month (9.5% vs. 11.5% [p=0.163]). Diarrhea was the only reported side effect, occurring in 6.5% of patients in the colchicine group. Conclusion: Low-dose colchicine administration in anterior STEMI patients undergoing PPCI did not reduce LV adverse remodeling or systolic function. Keyword: Adverse Remodeling, Colchicine, Reperfusion Injury, STEMI, Systolic Function.
... However, the early effect of colchicine on residual inflammation has not been compared with aspirin, which is recommended after PCI. In addition to its anti-inflammatory effect, colchicine possesses antithrombotic properties which may contributed to its effects on cardiovascular outcomes (19,20). Recently, the Mono-Antiplatelet and Colchicine Therapy (MACT) pilot trial demonstrated the feasibility of omitting aspiring and maintaining single antiplatelet therapy with ticagrelor or prasugrel combined with colchicine in ACS patients undergoing PCI (21). ...
Background
In patients undergoing percutaneous coronary intervention (PCI), the use of anti-inflammatory therapy with colchicine is associated with a reduction of recurrent ischemic events. The mechanisms of such findings are not fully elucidated.
Objectives
To investigate the effects of colchicine versus aspirin on inflammation and platelet reactivity in patients with acute coronary syndrome (ACS) undergoing PCI.
Methods
This observational study compared laboratory measurements in ACS patients receiving single antiplatelet therapy with ticagrelor or prasugrel plus colchicine (MACT) (n = 185) versus conventional dual-antiplatelet therapy (DAPT) with aspirin plus ticagrelor or prasugrel (n = 497). The primary outcome was the frequency of high residual inflammation, defined as high-sensitivity C-reactive protein (hs-CRP) ≥2 mg/L at 1 month post-PCI. Multiple sensitivity analyses were performed for the primary outcome, including multivariable adjustment, propensity-score matching, and inverse-probability weighted methods.
Results
One month after PCI, patients treated with MACT had significantly lower levels of hs-CRP compared to those treated with DAPT (0.6 [0.4–1.2] vs. 0.9 [0.6–2.3] mg/L, p < 0.001). The frequency of high residual inflammation was also lower in the MACT group (10.8% vs. 27.2%, p < 0.001) (odds ratio [95% confidence interval] = 0.33 [0.20–0.54], p < 0.001). This effect was consistent across sensitivity analyses. There was no difference in platelet reactivity between MACT and DAPT (49.6 ± 49.0 vs. 51.5 ± 66.4 P2Y12 reaction unit [PRU] measured by VerifyNow, p = 0.776).
Conclusion
In ACS patients undergoing PCI, MACT was associated with a lower rate of high residual inflammation without increasing platelet reactivity compared to conventional DAPT.
Clinical trial registration
NCT04949516 for MACT pilot trial and NCT04650529 for Gyeongsang National University Hospital registry.
... Colchicine is a commonly used oral anti-inflammatory drug with a long history, which plays an anti-inflammatory role by inhibiting the aggregation of microtubules [4]. Four independent randomized controlled trials (RCTs) [Low-Dose Colchicine (LoDoCo), LoDoCo2, Colchicine Cardiovascular Outcomes Trial (COLCOT), and Colchicine in Patients With Acute Coronary Syndromes (COPS)] evaluating the effect of colchicine in a broad spectrum of >11,000 patients with acute and chronic coronary artery disease (CAD) followed for up to 5 years, demonstrated that colchicine may reduce the risk of cardiovascular death, myocardial infarction, ischemic stroke and ischemia-driven revascularization by >30 % [5]. The 2021 European Society of Cardiology guidelines recommended that low-dose colchicine (0.5 mg/d orally) be considered for secondary prevention (IIb Class, A Level) [6]. ...
... With evolving understanding of atherosclerosis, targeting inflammation has become a pivotal therapeutic strategy in patients with atherosclerosis. In a combined analysis of trials of low-dose colchicine for CVD, a highly statistically significant more than 30 % reduction in myocardial infarction, stroke, coronary revascularization, or cardiovascular death was reported [5]. These magnitudes of benefit are larger than those seen in contemporary secondary prevention trials of adjunctive lipid-lowering medication [20]. ...
Background
Low-dose colchicine has been shown to lower major adverse cardiovascular events (MACE) among those with cardiovascular disease (CVD). It remains unclear how long a CVD patient needs to live to potentially benefit from colchicine. Our study aimed to determine the time to benefit (TTB) of colchicine in individuals with CVD.
Methods
Literature searches were performed in PubMed for the cardiovascular outcome trial of colchicine in patients with CVD until October 12, 2023. The primary outcome measured was MACE. Reconstructed individual participant data (IPD) and the stratified Cox proportional hazards model were used to calculate the hazard ratio (HR) and 95 % confidence interval (CI) to estimate the efficacy of colchicine, and Weibull survival curves were fitted to estimate TTB for specific absolute risk reduction (ARR) thresholds (0.002, 0.005, and 0.01).
Results
Four trials randomizing 11,594 adults aged between 59.8 and 66.5 years were included (follow-up duration: 12–28.6 months). Compared with placebo, colchicine reduced the risk of MACE (HR 0.68, 95 % CI: 0.60 to 0.78) but had no impact on cardiovascular and all-cause mortality. A TTB of 11.0 months (95 % CI: 0.59 to 21.3) was estimated to be needed to prevent 1 MACE in 100-colchicine-treated patients. The TTB for acute coronary syndrome was similar compared to stable coronary artery disease (10.7 vs. 11.2 months for ARR = 0.010).
Conclusions
By using reconstructed IPD, this pooled analysis demonstrated that colchicine was associated with reduced nonfatal MACE, and the TTB was approximately 11.0 months to prevent 1 MACE per 100 patients.
... Colchicine is a well-known drug, that could halve the recurrence rate, acting also as a non-specific inhibitor of the inflammasome, the cytosolic complex that generates IL-1 after activation. 8 Based on several spontaneous clinical trials the efficacy and safety of colchicine has been well documented either in acute or RP 9-12 leading to a strong recommendation of class I, level of evidence A to use colchicine on top of standard anti-inflammatory therapy in patients with acute and RP to prevent recurrences. 13 Colchicine interferes with the generation of IL-1 by inhibiting the activation of the inflammasome, that triggers IL-1 activation. ...
Aim
Anakinra, an anti IL-1 agent targeting IL-1 alfa and beta, is available for the treatment of recurrent pericarditis in cases with corticosteroid dependence and colchicine resistance after failure of conventional therapies. However, it is unclear if the combination with colchicine, a non-specific inhibitor of the inflammasome targeting the same inflammatory pathway of IL-1, could provide additional benefit to prevent further recurrences. The aim of the present observational study is to assess whether the addition of colchicine on top of anakinra could prolong the time to first recurrence and prevent recurrences better than anakinra alone.
Methods
International, all-comers, multicentre, retrospective observational cohort study analysing all consecutive patients treated with anakinra for corticosteroid-dependent and colchicine-resistant recurrent pericarditis. The efficacy endpoint was recurrence rate and the time to the first recurrence.
Results
A total of 256 patients (mean age 45.0±15.4 years, 65.6% females, 80.9% with idiopathic/viral aetiology) were included. 64 (25.0%) were treated with anakinra as monotherapy while 192 (75.0%) with both anakinra and colchicine. After a follow-up of 12 months, 56 (21.9%) patients had recurrences. Patients treated with colchicine added to anakinra had a lower incidence of recurrences (respectively, 18.8% vs 31.3%; p=0.036) and a longer event-free survival (p=0.025). In multivariable analysis, colchicine use prevented recurrences (HR 0.52, 95% CI 0.29 to 0.91; p=0.021).
Conclusions
The addition of colchicine on top of anakinra treatment could be helpful to reduce recurrences and prolong the recurrence-free survival.
... One approach is to inhibit NETosis, the process by which neutrophils release NETs. For example, colchicine, an antiinflammatory agent, can bind to tubulin and disrupt the formation of NETs [129]. Another compound called chloramidine inhibits PAD4, a key enzyme in NETosis, and has shown efficacy in reducing atherosclerotic lesions in animal models [130]. ...
Neutrophil extracellular traps (NETs) are network-like structures released by activated neutrophils. They consist mainly of double-stranded DNA, histones, and neutrophil granule proteins. Continuous release of NETs in response to external stimuli leads to activation of surrounding platelets and monocytes/macrophages, resulting in damage to endothelial cells (EC) and vascular smooth muscle cells (VSMC). Some clinical trials have demonstrated the association between NETs and the severity and prognosis of atherosclerosis. Furthermore, experimental findings have shed light on the molecular mechanisms by which NETs contribute to atherogenesis. NETs play a significant role in the formation of atherosclerotic plaques. This review focuses on recent advancements in the understanding of the relationship between NETs and atherosclerosis. It explores various aspects, including the formation of NETs in atherosclerosis, clinical trials investigating NET-induced atherosclerosis, the mechanisms by which NETs promote atherogenesis, and the translational implications of NETs. Ultimately, we aim to propose new research directions for the diagnosis and treatment of atherosclerosis.
... No estudo realizado por Ferreira et al. (2022), a colchicina (COL) foi utilizada como controle positivo. A COL representa um medicamento singular e refinado, com propriedades antiinflamatórias distintas, sendo empregado por várias décadas na prevenção de episódios agudos de inflamação (Slobodnick et al., 2018;Imazio;Nidorf, 2021), mas na citotoxicologia é conhecida por interferir na divisão celular normal, inibindo a formação do fuso mitótico e levando à formação de células poliploides com anormalidades cromossômicas, como pontes cromossômicas, fragmentos, micronúcleos. ...
... No estudo realizado por Ferreira et al. (2022), a colchicina (COL) foi utilizada como controle positivo. A COL representa um medicamento singular e refinado, com propriedades antiinflamatórias distintas, sendo empregado por várias décadas na prevenção de episódios agudos de inflamação (Slobodnick et al., 2018;Imazio;Nidorf, 2021), mas na citotoxicologia é conhecida por interferir na divisão celular normal, inibindo a formação do fuso mitótico e levando à formação de células poliploides com anormalidades cromossômicas, como pontes cromossômicas, fragmentos, micronúcleos. ...
O Allium cepa L. é um bioindicador amplamente empregado em estudos biológicos devido à sua sensibilidade a agentes tóxicos. A confiabilidade desses ensaios é crucial e exige a validação por meio de controles positivos. Este estudo constitui-se em uma revisão integrativa da literatura, cuja busca foi realizada nas bases de dados PubMed, SciELO, BVS e LILACS e objetivou identificar as substâncias mais comumente utilizadas como controles positivos em pesquisas que empregam o teste Allium cepa L. Foram incluídos artigos que respondessem à questão norteadora: "Quais são as principais substâncias utilizadas como controles positivos nos ensaios de toxicidade com Allium cepa L.?". Dez estudos foram incluídos, destacando substâncias como Metanossulfonato de metila, Azida Sódica, Colchicina e outras. Os resultados revelaram variados danos celulares induzidos por diferentes substâncias. A interpretação precisa desses ensaios deve considerar nuances, incluindo a variedade específica de cebola e as concentrações das substâncias. Este estudo enfatiza a importância dessas informações para que pesquisas adicionais e a aplicação mais precisar do teste Allium cepa L. na avaliação da toxicidade.
