The role of colchicine in the management of COVID-19: a Meta-analysis.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic has robustly affected the global healthcare and economic systems and it was caused by coronavirus-2 (SARS-CoV-2). The clinical presentation of the disease ranges from a flu-like illness to severe pneumonia and death. Till September 2022, the cumulative number of cases exceeded 600 million worldwide and deaths were more than 6 million. Colchicine is an alkaloid drug that is used in many autoinflammatory conditions e.g., gout, familial Mediterranean fever, and Behçet's syndrome. Colchicine inhibits the production of superoxide and the release of interleukins that stimulate the inflammatory cascade. Colchicine decreases the differentiation of myofibroblast and the release of fibrotic mediators including transforming growth factor (TGF-ß1) that are related to the fibrosis. Moreover, colchicine has been used to traet viral myocarditis caused by CMV or EBV, interstitial pneumonia, and pericarditis resulting from influenza B infection. Additionally, colchicine is considered safe and affordable with wide availability. OBJECTIVE: The aim of the current study was to assess the evidence of colchicine effectiveness in COVID-19 treatment. METHODS: A comprehensive review of the literature was done till May 2022 and yielded 814 articles after ranking the articles according to authors and year of publication. Only 8 clinical trials and cohort studies fulfilling the inclusion criteria were included for further steps of data collection, analysis, and reporting. RESULTS: This meta-analysis involved 16,488 patients; 8146 patients in the treatment group and 8342 patients in the control group. The results showed that colchicine resulted in a significant reduction in the mortality rate among patients received colchicine in comparison with placebo or standard care (RR 0.35, 95%CI: 0.15-0.79). Colchicine resulted in a significant decrease in the need for O2 therapy in patients with COVID-19 (RR 0.07, 95%CI 0.02-0.27, P = 0.000024). However, colchicine had no significant effect on the following outcomes among COVID-19 patients: the need for hospitalization, ICU admission, artificial ventilation, and hospital discharge rate. Among the PCR confirmed COVID-19 patients, colchicine decreased the hospitalization rate (RR 0.75, 95%CI 0.57-0.99, P = 0.042). However, colchicine had no effect on mortality and the need for mechanical ventilation among this subgroup. CONCLUSION: Colchicine caused a significant clinical improvement among COVID-19 patients as compared with the standard care or placebo, in terms of the need for O2, and mortality. This beneficial effect could play a role in the management of COVID-19 especially severe cases to decrease need for oxygen and to decrease mortality among these patients.

Colchicine for the treatment of patients with COVID-19: an updated systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: We conducted an updated systematic review and meta-analysis to investigate the effect of colchicine treatment on clinical outcomes in patients with COVID-19. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Embase, the Cochrane Library, medRxiv and ClinicalTrials.gov from inception to January 2023. ELIGIBILITY CRITERIA: All randomised controlled trials (RCTs) that investigated the efficacy of colchicine treatment in patients with COVID-19 as compared with placebo or standard of care were included. There were no language restrictions. Studies that used colchicine prophylactically were excluded. DATA EXTRACTION AND SYNTHESIS: We extracted all information relating to the study characteristics, such as author names, location, study population, details of intervention and comparator groups, and our outcomes of interest. We conducted our meta-analysis by using RevMan V.5.4 with risk ratio (RR) and mean difference as the effect measures. RESULTS: We included 23 RCTs (28 249 participants) in this systematic review. Colchicine did not decrease the risk of mortality (RR 0.99; 95% CI 0.93 to 1.05; I2=0%; 20 RCTs, 25 824 participants), with the results being consistent among both hospitalised and non-hospitalised patients. There were no significant differences between the colchicine and control groups in other relevant clinical outcomes, including the incidence of mechanical ventilation (RR 0.75; 95% CI 0.48 to 1.18; p=0.22; I2=40%; 8 RCTs, 13 262 participants), intensive care unit admission (RR 0.77; 95% CI 0.49 to 1.22; p=0.27; I2=0%; 6 RCTs, 961 participants) and hospital admission (RR 0.74; 95% CI 0.48 to 1.16; p=0.19; I2=70%; 3 RCTs, 8572 participants). CONCLUSIONS: The results of this meta-analysis do not support the use of colchicine as a treatment for reducing the risk of mortality or improving other relevant clinical outcomes in patients with COVID-19. However, RCTs investigating early treatment with colchicine (within 5 days of symptom onset or in patients with early-stage disease) are needed to fully elucidate the potential benefits of colchicine in this patient population. PROSPERO REGISTRATION NUMBER: CRD42022369850.

High systemic inflammation as a novel cardiovascular risk factor and target for anti-cytokine therapy: comment regarding the triglyceride glucose index.

In the last century, there has been more than enough research that proved the association of high lipid and glucose levels with cardiovascular disease, thus establishing the current well-known traditional cardiovascular risk factors such as dyslipidemia, diabetes, and metabolic syndrome. Hence, these cardiovascular risk factors are target therapy for glucose and lipid-lowering agents to prevent adverse cardiovascular events. However, despite controlling the lipid and glucose levels, some studies demonstrated the subclinical atherosclerosis suggesting that these cardiovascular risk factors alone cannot account for the entire atherosclerosis burden. In the last years, large-scale clinical trials demonstrated the operation of the inflammatory pathway in atherosclerotic cardiovascular disease (ASCVD) by the immune system, both the innate (neutrophils, macrophages) and adaptive (T cell and other lymphocytes) limbs, contribute to atherosclerosis and atherothrombosis. In this regard, some studies that use antiinflammatory therapy targeting the immune system by modulating or blocking interleukins, also known as anti-cytokine therapy, have been shown to reduce the risk of adverse cardiovascular events in patients with previous coronary artery disease. In this regard, the U.S. Food and Drug Administration (FDA) approved the use of colchicine 0.5 mg once daily for reducing cardiovascular events in patients who have established ASCVD and high residual systemic inflammation. Therefore, measuring the systemic inflammation can improve the cardiovascular risk assessment and identify the subsets of patients that will benefit from anti-cytokine therapy after diagnosis of ASCVD or after myocardial revascularization.

Prednisolone Versus Colchicine for Acute Gout in Primary Care: statistical analysis plan for the pragmatic, multicenter, randomized, and double-blinded COPAGO non-inferiority trial.

BACKGROUND: To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen. STUDY DESIGN: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed. STATISTICAL ANALYSIS PLAN: N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0-10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients' global assessment of treatment success are secondary outcomes. DISCUSSION: The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered).

Integrative Inducer Intervention and Transcriptomic Analyses Reveal the Metabolism of Paralytic Shellfish Toxins in Azumapecten farreri.

Paralytic shellfish toxins (PSTs) are widely distributed neurotoxins, and the PST metabolic detoxification mechanism in bivalves has received increasing attention. To reveal the effect of phase I (cytochrome P450)-II (GST)-III (ABC transport) metabolic systems on the PST metabolism in Azumapecten farreri, this study amplified stress on the target systems using rifampicin, dl-α-tocopherol, and colchicine; measured PST levels; and conducted transcriptomic analyses. The highest toxin content reached 1623.48 µg STX eq/kg in the hepatopancreas and only 8.8% of that in the gills. Inducer intervention significantly decreased hepatopancreatic PST accumulation. The proportional reductions in the rifampicin-, dl-α-tocopherol-, and colchicine-induced groups were 55.3%, 50.4%, and 36.1%, respectively. Transcriptome analysis showed that 11 modules were significantly correlated with PST metabolism (six positive/five negative), with phase I CYP450 and phase II glutathione metabolism significantly enriched in negatively correlated pathways. Twenty-three phase I-II-III core genes were further validated using qRT-PCR and correlated with PST metabolism, revealing that CYP46A1, CYP4F6, GSTM1, and ABCF2 were significantly correlated, while CYP4F11 and ABCB1 were indirectly correlated. In conclusion, phase I-II-III detoxification enzyme systems jointly participate in the metabolic detoxification of PSTs in A. farreri. This study provides key data support to profoundly elucidate the PST metabolic detoxification mechanism in bivalves.

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis.

Development of non-surgical treatment of human abdominal aortic aneurysm (AAA) has clinical significance. Colchicine emerges as an effective therapeutic regimen in cardiovascular diseases. Yet, whether colchicine slows AAA growth remain controversy. Here, we demonstrated that daily intragastric administration of low-dose colchicine blocked AAA formation, prevented vascular smooth muscle cell (SMC) phenotype switching and apoptosis, and vascular inflammation in both peri-aortic CaPO4 injury and subcutaneous angiotensin-II infusion induced experimental AAA mice models. Mechanistically, colchicine increased global mRNA stability by inhibiting the METTL14/YTHDC1-mediated m6A modification, resulting in increased sclerostin (SOST) expression and consequent inactivation of the WNT/ß-catenin signaling pathway in vascular SMCs from mouse AAA lesions and in cultured human aortic SMCs. Moreover, human and mouse AAA lesions all showed increased m6A methylation, decreased SOST expression, and skewed synthetic SMC de-differentiation phenotype, compared to those without AAA. This study uncovers a novel mechanism of colchicine in slowing AAA development by using the METTL14/SOST/WNT/ß-catenin axis to control vascular SMC homeostasis in mouse aortic vessels and in human aortic SMCs. Therefore, use of colchicine may benefit AAA patients in clinical practice.

Anthelmintic screening of Bangladeshi medicinal plants and related phytochemicals using in vitro and in silico methods: An ethnobotanical perspective.

ETHNOPHARMACOLOGICAL RELEVANCE: Infections caused by parasitic worms or helminth continue to pose a great burden on human and animal health, particularly in underdeveloped tropical and subtropical countries where they are endemic. Current anthelmintic drugs present serious limitations and the emergence of drug resistance has made it increasingly challenging to combat such infections (helminthiases). In Bangladesh, medicinal plants are often used by indigenous communities for the treatment of helminthiases. Knowledge on such plants along with screening for their anthelmintic activity has the potential to lead to the discovery of phytochemicals that could serve as novel molecular scaffolds for the development of new anthelminthic drugs. AIM OF THE STUDY: The purpose of this study was i) to conduct an ethnobotanical survey to gather data on Bangladeshi medicinal plants used in the treatment of helminthiases, ii) to test plants with the highest use values for their in vitro anthelmintic activity, and iii) to carry out in silico screening on phytochemicals present in the most active plant extract to investigate their ability to disrupt ß-tubulin function in helminths. METHODS: The ethnobotanical survey was conducted across three sub-districts of Bangladesh, namely Mathbaria, Phultala and Khan Jahan Ali. The in vitro screening for anthelmintic activity was performed in a motility test using adult Haemonchus contortus worms. Virtual screening using PyRx was performed on the phytochemicals reported from the most active plant, exploring their interactions with the colchicine binding site of the ß-tubulin protein target (PDB ID: 1SA0). RESULTS: The survey respondents reported a total of 32 plants for treating helminthiases. Based on their use values, the most popular choices were Ananas comosus (L.) Merr., Azadirachta indica A.Juss., Carica papaya L., Citrus maxima (Burm.) Merr., Curcuma longa L., Momordica charantia L., Nigella sativa L. and Syzygium cumini (L.) Skeels. In vitro anthelmintic testing revealed that A. indica leaves and bark had the highest activity with LC50 values of 16 mg/mL in both cases. Other plant extracts also exhibited good anthelmintic activity with LC50 values ranging from 16 to 52 mg/mL, while the value for albendazole (positive control) was 8.39 mg/mL. The limonoids nimbolide and 28-deoxonimbolide showed a binding affinity of -8.9 kcal/mol, and satisfied all drug-likeness parameters. The control ligand N-deacetyl-N-(2-mercaptoacetyl)colchicine had a binding affinity of -6.9 kcal/mol. CONCLUSION: Further in silico and in vitro studies are warranted on the identified limonoids to confirm the potential of these derivatives as novel drug templates for helminthiases. The current study supports the need for an ethnobotanical survey-based approach to discover novel drug templates for helminthiases.

Structure-based approaches for the design of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazoles as tubulin polymerization inhibitors.

The colchicine binding site on tubulin has been widely acknowledged as an attractive target for anticancer drug exploitation. Here, we reported the structural optimization of the lead compound 4, which was proved in our previous work as a colchicine binding site inhibitor (CBSI). Based on docking researches for the active binding conformation of compound 4, a series of novel 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazole derivatives (9a-9x) were developed by replacing a CH group in the 1H-benzo[d]imidazole skeleton of compound 4 with a nitrogen atom as a hydrogen bond acceptor. Among them, compound 9a showed the strongest antiproliferative activity with IC50 values ranging from 14 to 45 nM against three human cancer cell lines (MCF-7, SGC-7901 and A549), lower than that of compound 4. Mechanistic studies indicated that compound 9a could inhibit tubulin polymerization, destroy the microtubule skeleton, block the cell cycle in G2/M phase, induce cancer cell apoptosis, prevent cancer cell migration and colony formation. Moreover, compound 9a significantly inhibited tumor growth in vivo without observable toxicity in the mice 4T1 xenograft tumor model. In conclusion, this report shows a successful case of the structure-based design approach of a potent tubulin polymerization inhibitor for cancer treatment.

Autotetraploid Induction of Three A-Genome Wild Peanut Species, Arachis cardenasii, A. correntina, and A. diogoi.

A-genome Arachis species (AA; 2n = 2x = 20) are commonly used as secondary germplasm sources in cultivated peanut breeding, Arachis hypogaea L. (AABB; 2n = 4x = 40), for the introgression of various biotic and abiotic stress resistance genes. Genome doubling is critical to overcoming the hybridization barrier of infertility that arises from ploidy-level differences between wild germplasm and cultivated peanuts. To develop improved genome doubling methods, four trials of various concentrations of the mitotic inhibitor treatments colchicine, oryzalin, and trifluralin were tested on the seedlings and seeds of three A-genome species, A. cardenasii, A. correntina, and A. diogoi. A total of 494 seeds/seedlings were treated in the present four trials, with trials 1 to 3 including different concentrations of the three chemical treatments on seedlings, and trial 4 focusing on the treatment period of 5 mM colchicine solution treatment of seeds. A small number of tetraploids were produced from the colchicine and oryzalin gel treatments of seedlings, but all these tetraploid seedlings reverted to diploid or mixoploid states within six months of treatment. In contrast, the 6-h colchicine solution treatment of seeds showed the highest tetraploid conversion rate (6-13% of total treated seeds or 25-40% of surviving seedlings), and the tetraploid plants were repeatedly tested as stable tetraploids. In addition, visibly and statistically larger leaves and flowers were produced by the tetraploid versions of these three species compared to their diploid versions. As a result, stable tetraploid plants of each A-genome species were produced, and a 5 mM colchicine seed treatment is recommended for A-genome and related wild Arachis species genome doubling.

Colchicine's Role in Cardiovascular Disease Management.

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.

Design, synthesis and biological evaluation of new 2,6-difluorinated phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new antimicrotubule agents.

We previously discovered a novel family of antimicrotubule agents designated as phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). In this study, we evaluated the effect of the difluorination of the aromatic ring bearing the imidazolidin-2-one moiety (ring A) at positions 3, 5 and 2, 6 on their antiproliferative activity on four cancer cell lines, their ability to disrupt the microtubules and their toxicity toward chick embryos. We thus synthesized, characterized and biologically evaluated 24 new difluorinated PIB-SO derivatives designated as phenyl 3,5-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (3,5-PFB-SOs, 4-15) and phenyl 2,6-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (2,6-PFB-SOs, 16-27). The concentration of the drug required to inhibit cell growth by 50% (IC50) of 3,5-PFB-SOs is over 1000 nM while most of 2,6-PFB-SOs exhibit IC50 in the nanomolar range (23-900 nM). Furthermore, the most potent 2,6-PFB-SOs 19, 26 and 27 arrest the cell cycle progression in G2/M phase, induce cytoskeleton disruption and impair microtubule polymerization. Docking studies also show that the most potent 2,6-PFB-SOs 19, 21, 24, 26 and 27 have binding affinity toward the colchicine-binding site (C-BS). Moreover, their antiproliferative activity is not affected by antimicrotubule- and multidrug-resistant cell lines. Besides, they exhibit improved in vitro hepatic stability in the mouse, rat and human microsomes compared to their non-fluorinated counterparts. They also showed theoretical pharmacokinetic, physicochemical and drug-like properties suited for further in vivo assays. In addition, they exhibit low to no systemic toxicity toward chick embryos. Finally, our study evidences that PIB-SOs must be fluorinated in specific positions on ring A to maintain both their antiproliferative activity and their biological activity toward microtubules.

Efficacy of colchicine in addition to anakinra in patients with recurrent pericarditis.

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.

Meta-Analysis of Randomized Trials: Efficacy and Safety of Colchicine for Secondary Prevention of Cardiovascular Disease.

Background: Colchicine has shown potential cardioprotective effects owing to its broad anti-inflammatory properties. We performed a meta-analysis to assess its safety and efficacy in secondary prevention in patients with established coronary artery disease (CAD). Methods: We searched Ovid Healthstar, MEDLINE, and Embase (inception to May 2022) for randomized controlled trials (RCTs) evaluating the cardiovascular effects of colchicine compared with placebo or usual care in patients with CAD. Study-level data on efficacy and safety outcomes were pooled using the Peto method. The primary outcome was the composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke. Results: A total of 8 RCTs were included with a follow-up duration of ≥1 month, comprising a total of 12,151 patients. Compared with placebo or usual care, colchicine was associated with a significant risk reduction in the primary outcome (odds ratio (OR) 0.70, 95% CI 0.60 to 0.83, P < 0.0001; I2 = 52%). Risks of MI (OR 0.75, 95% CI 0.62 to 0.91, P = 0.003; I2 = 33%), stroke (OR 0.47, 95% CI 0.30 to 0.74, P = 0.001; I2 = 0%), and unplanned coronary revascularization (OR 0.67, 95% CI 0.55 to 0.82, P = 0.0001; I2 = 58%) were all reduced in the colchicine group. Rates of CV and all-cause mortality did not differ between the two groups, but there was an increase in noncardiac deaths with colchicine (OR 1.54, 95% CI 1.10 to 2.15, P = 0.01; I2 = 51%). The occurrence of all other adverse events was similar between the two groups, including GI reactions (OR 1.06, 95% CI 0.94 to 1.20, P = 0.35; I2 = 42%) and infections (OR 1.04, 95% CI 0.84 to 1.28, P = 0.74; I2 = 53%). Conclusions: Colchicine therapy may reduce the risk of future cardiovascular events in patients with established CAD; however, there remains a concern about non-CV mortality. Further trials are underway that will shed light on non-CV mortality and colchicine NCT03048825, and NCT02898610.

Structure-based design and synthesis of BML284 derivatives: A novel class of colchicine-site noncovalent tubulin degradation agents.

Our previous studies have demonstrated that BML284 is a colchicine-site tubulin degradation agent. To improve its antiproliferative properties, 45 derivatives or analogs of BML284 were designed and synthesized based on the cocrystal structure of BML284 and tubulin. Among them, 5i was the most potent derivative, with IC50 values ranging from 0.02 to 0.05 µM against the five tested tumor cell lines. Structure-activity relationship studies verified that the N1 atom of the pyrimidine ring was the key functional group for its tubulin degradation ability. The 5i-tubulin cocrystal complex revealed that the binding pattern of 5i to tubulin is similar to that of BML284. However, replacing the benzodioxole ring with an indole ring strengthened the hydrogen bond formed by the 2-amino group with E198, which improved the antiproliferative activity of 5i. Compound 5i effectively suppressed tumor growth at an intravenous dose of 40 mg/kg (every 2 days) in paclitaxel sensitive A2780S and paclitaxel resistant A2780T ovarian xenograft models, with tumor growth inhibition values of 79.4% and 82.0%, respectively, without apparent side effects, showing its potential to overcome multidrug resistance. This study provided a successful example of crystal structure-guided discovery of 5i as a colchicine-targeted tubulin degradation agent, expanding the scope of targeted protein degradation.

Update on the Role of Colchicine in Cardiovascular Disease.

PURPOSE OF REVIEW: This review focuses on the use of colchicine to target inflammation to prevent cardiovascular events among those at-risk for or with established coronary artery disease. RECENT FINDINGS: Colchicine is an anti-inflammatory drug that reduces cardiovascular events through its effect on the IL-1ß/IL-6/CRP pathway, which promotes the progression and rupture of atherosclerotic plaques. Clinical trials have demonstrated that colchicine reduces cardiovascular events by 31% among those with chronic coronary disease, and by 23% among those with recent myocardial infarction. Its ability to dampen inflammation during an acute injury may broaden its scope of use in patients at risk for cardiovascular events after major non-cardiac surgery. Colchicine is an effective anti-inflammatory therapy in the prevention of acute coronary syndrome. Ongoing studies aim to assess when, and in whom, colchicine is most effective to prevent cardiovascular events in patients at-risk for or with established coronary artery disease.

Investigating the Promising Anticancer Activity of Cetuximab and Fenbendazole Combination as Dual CBS and VEGFR-2 Inhibitors and Endowed with Apoptotic Potential.

In this work, the cytotoxicity of monoclonal antibody (Cetuximab, Ce) and Fenbendazole (Fen), as well as their combination therapy were tested with the MTT assay. On the other side, Ce, Fen, and a combination between them were subjected to a colchicine-tubulin binding test, which was conducted and compared to Colchicine as a reference standard. Besides, Ce, Fen, and the combination of them were tested against the VEGFR-2 target receptor, compared to Sorafenib as the standard medication. Moreover, the qRT-PCR technique was used to investigate the levels of apoptotic genes (p53 and Bax) and anti-apoptotic gene (Bcl-2) as well. Also, the effect of Ce, Fen, and the combination of them on the level of ROS was studied. Furthermore, the cell cycle analysis and Annexin V apoptosis assay were carried out for Ce, Fen, and a combination of them. In addition, the molecular docking studies were used to describe the molecular levels of interactions for both (Fen and colchicine) or (Fen and sorafenib) within the binding pockets of the colchicine binding site (CBS) and vascular endothelial growth factor-2 receptor (VEGFR-2), respectively.

Gout: one year in review 2023.

Gout is a chronic joint disease caused by the deposition of monosodium urate crystals into and around the articular tissues. In the last two years, new insights regarding diagnosis, genetic involvement, pathogenesis, comorbidities, and clinical data, have allowed the identification of new strategies to improve the control of the disease and its flares. In keeping, the discover of new mechanisms concerning crystal-induced inflammation have suggested new ways for the management not only of gout, but also other systemic diseases, mainly including renal and cardiovascular disorders. In this context it is very representative the case of colchicine which, given the surprising results obtained both in laboratory and clinical experiments, has recently received by FDA the approval for the prevention of cardiovascular disorders.

Network Pharmacology Analysis of the Therapeutic Potential of Colchicine in Acute Lung Injury.

Background: This study employed integrated network pharmacology approach to explore the mechanisms underlying the protective effect of colchicine against acute lung injury (ALI). Methods: We analyzed the expression profiles from 13 patients with sepsis-related ALI and 21 controls to identify differentially expressed genes and key modules. ALI-related genes were curated using databases such as DisGeNET, Therapeutic Target, and Comparative Toxicogenomics Database to curate ALI-related genes. Drug target fishing for colchicine was conducted using the DrugBank, BATMAN-TCM, STITCH, and SwissTargetPrediction. Potential drug-disease interactions were determined by intersecting ALI-associated genes with colchicine target genes. We performed comprehensive pathway and process enrichment analyses on these genes. A protein-protein interaction network was constructed, and topological analysis was executed. Additionally, an ALI mouse model was established to evaluate the effect of colchicine on CXCL12 and CXCR4 levels through western blot analysis. Results: Analysis revealed 23 potential colchicine-ALI interaction genes from the intersection of 253 ALI-associated genes and 389 colchicine targets. Functional enrichment analysis highlighted several inflammation-related pathways, such as cytokine-mediated signaling pathway, CXCR chemokine receptor binding, NF-kappa B signaling pathway, TNF signaling pathway, and IL-17 signaling pathway. The protein-protein interaction network demonstrated complex interactions for CXCL12 and CXCR4 among other candidate genes, with significant topological interaction degrees. In vivo studies showed that colchicine significantly reduced elevated CXCL12 and CXCR4 levels in ALI mice. Conclusion: Our findings suggest that colchicine's therapeutic effect on ALI might derive from its anti-inflammatory properties. Further research is needed to explore the specific mechanisms of colchicine's interaction with sepsis-induced ALI.

Impact of the 2021 European Society for Cardiology prevention guideline's stepwise approach for cardiovascular risk factor treatment in patients with established atherosclerotic cardiovascular disease.

AIMS: This study aimed to evaluate the stepwise approach for cardiovascular (CV) risk factor treatment as outlined by the European Society for Cardiology 2021 guidelines on CV disease (CVD) prevention in patients with established atherosclerotic CVD (ASCVD). METHODS AND RESULTS: In patients with ASCVD, included in UCC-SMART (n = 8730) and European parts of the REACH registry (n = 18 364), the 10-year CV risk was estimated using SMART2. Treatment effects were derived from meta-analyses and trials. Step 1 recommendations were LDL cholesterol (LDLc) < 1.8 mmol/L, systolic blood pressure (SBP) < 140 mmHg, using any antithrombotic medication, sodium-glucose co-transporter 2 (SGLT2) inhibition, and smoking cessation. Step 2 recommendations were LDLc < 1.4 mmol/L, SBP < 130 mmHg, dual-pathway inhibition (DPI, aspirin plus low-dose rivaroxaban), colchicine, glucagon-like peptide (GLP)-1 receptor agonists, and eicosapentaenoic acid. Step 2 was modelled accounting for Step 1 non-attainment. With current treatment, residual CV risk was 22%, 32%, and 60% in the low, moderate, and pooled (very) high European risk regions, respectively. Step 2 could prevent up to 198, 223 and 245 events per 1000 patients treated, respectively. Intensified LDLc reduction, colchicine, and DPI could be applied to most patients, preventing up to 57, 74, and 59 events per 1000 patients treated, respectively. Following Step 2, the number of patients with a CV risk of <10% could increase from 20%, 6.4%, and 0.5%, following Step 1, to 63%, 48%, and 12%, in the respective risk regions. CONCLUSION: With current treatment, residual CV risk in patients with ASCVD remains high across all European risk regions. The intensified Step 2 treatment options result in marked further reduction of residual CV risk in patients with established ASCVD. KEY FINDINGS: Guideline-recommended intensive treatment of patients with cardiovascular disease could prevent additional 198-245 new cardiovascular events for every 1000 patients treated.

Patients with established cardiovascular disease are at high risk for new cardiovascular events. The European Society of Cardiology guideline for the prevention of cardiovascular disease introduced a stepwise treatment approach. Step 1 in this approach are treatments that apply to all patients, and Step 2 are intensive treatments that can be prescribed to patients who are still at high risk of new events even with Step 1 treatments. The current study investigates the effect of Steps 1 and 2 on the risk of cardiovascular disease in 27 094 patients all across Europe. With the conventional treatments of Step 1 the risk of cardiovascular disease remains high, with a 10-year risk of new events higher than 10% in 80­99% of patients. The intensive treatment options from Step 2 could prevent additional 198­245 new cardiovascular events for every 1000 patients that are treated. With intensive treatment, up to 63% of patients could achieve a 10-year risk of new cardiovascular disease below 10%.