Drug-Drug Interactions and the Clinical Tolerability of Colchicine Among Patients With COVID-19: A Secondary Analysis of the COLCORONA Randomized Clinical Trial.

Importance: Colchicine has many drug-drug interactions with commonly prescribed medications. Only pharmacokinetic studies have provided data on colchicine drug-drug interactions. Objective: To evaluate the clinical tolerability of colchicine according to the presence or absence of a drug-drug interaction. Design, Setting, and Participants: A secondary analysis of the COLCORONA trial was performed. The COLCORONA trial was a randomized, double-blind, placebo-controlled trial conducted in Brazil, Canada, Greece, South Africa, Spain, and the US between March 23, 2020, and January 20, 2021. The COLCORONA trial included ambulatory patients with COVID-19 with at least 1 high-risk characteristic and compared the effects of colchicine (0.5 mg twice daily for 3 days, then 0.5 mg daily thereafter) with placebo for 27 days. Data analysis was performed from February 24, 2023, to June 20, 2024. Exposure: In this secondary analysis, baseline medications that had interactions with colchicine were identified using a previously published expert classification. Main Outcomes and Measures: The primary outcome for this analysis was the composite of serious and nonserious treatment-related and treatment-unrelated gastrointestinal adverse events. The secondary outcomes were other adverse events and the composite of death or hospital admission due to COVID-19 infection. Logistic regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, heart failure, and myocardial infarction were assessed for effect modification of the association between the randomization arm and the outcomes of interest by drug-drug interaction status. Results: The cohort included 2205 participants in the colchicine arm and 2227 in the placebo arm (median age, 54 [IQR, 47-61] years; 2389 [54%] women). The most common colchicine drug-drug interactions were rosuvastatin (12%) and atorvastatin (10%). In fully adjusted models, the odds of any gastrointestinal adverse event were 1.80 (95% CI, 1.51-2.15) times higher in the colchicine arm than the placebo arm among people without a drug-drug interaction and 1.68 (95% CI, 1.24-2.26) times higher in the colchicine arm than the placebo arm among people with a drug-drug interaction (P = .69 for interaction). Drug-drug interaction status did not significantly modify the effect of colchicine on the composite of COVID-19 hospitalization or death (odds ratio, 0.91; 95% CI, 0.59-1.40 for drug-drug interaction and 0.84; 95% CI, 0.60-1.19 for no drug-drug interaction; P = .80 for interaction). Conclusions and Relevance: In this secondary analysis of the COLCORONA trial, operational classification of drug interactions system class 3 or 4 drug-drug interactions did not appear to significantly increase the risk of colchicine-related adverse effects. Trial Registration: ClinicalTrials.gov Identifier: NCT04322682.

Evaluation of the pharmacokinetics, chylomicron inhibition, and toxicity of colchicine in rats given low doses.

Colchicine (COL) is known for its ability to inhibit the formation of intestinal chylomicrons and has been utilized as a non-surgical tool to explore drug absorption via the intestinal lymphatics. However, there is limited understanding of its pharmacokinetics and its relationship to effect and toxicity with the doses used. This study aimed to provide comprehensive COL pharmacokinetic data and correlate it with the lymphatic-blocking and toxicological effects of low-doses. Male Sprague-Dawley rats with jugular-vein cannulation (JVC) received 0.1 to 0.5 mg/kg COL via oral, 0.25 mg/kg intraperitoneal, and 0.1 mg/kg intravenous routes, followed by blood and urine sampling for LC-MS/MS analysis. Effects on lipid absorption were assessed in another eight JVC rats receiving peanut oil with and without COL, followed by blood pharmacokinetic and plasma biochemistry analysis. The results revealed that COL exhibited moderate extraction ratio and high volume of distribution, with low oral bioavailability (<8%). About 20 % was recovered in the urine after parenteral dosing. Modest but significant reductions in cholesterol absorption was observed after oral doses of 0.5 mg/kg, accompanied by signs of inflammation and increased liver enzymes persisting for a week. The effect of COL on triglycerides formation was not significant. Despite its use as a non-surgical tool in rats to investigate drug absorption via the lymphatic pathway, COL demonstrated increased levels of liver function enzymes, emphasizing the need for caution and dose optimization in its utilization.

Transdermal delivery of iguratimod and colchicine ethosome by dissolving microneedle patch for the treatment of recurrent gout.

This study introduces a novel approach of repetitive modeling to simulate the pathological process of recurrent gout attacks in humans. This methodology addresses the instability issues present in rat models of gout, providing a more accurate representation of the damage recurrent gout episodes inflict on human skeletal systems. A soluble nanoneedle system encapsulating colchicine and iguratimod ethosomal formulations was developed. This system aims to modulate inflammatory cytokines and inhibit osteoclast activity, thereby treating inflammatory pain and bone damage associated with recurrent gout. Additionally, a comprehensive evaluation of the microneedles' appearance, morphology, mechanical properties, and penetration capability confirmed their effectiveness in penetrating the stratum corneum. Dissolution tests and skin irritation assessments demonstrated that these microneedles dissolve rapidly without irritating the skin. In vitro permeation studies indicated that transdermal drug delivery via these microneedles is more efficient and incurs lower drug loss compared to traditional topical applications. In vivo pharmacodynamic assessments conducted in animal models revealed significant analgesic and anti-inflammatory effects when both types of microneedles were used together. Further analyses, including X-ray imaging, hematoxylin and eosin (H&E) staining, Safranin-O/fast green staining, tartrate-resistant acid phosphatase staining, and quantification of osteoclasts, confirmed the bone-protective effects of the microneedle combination. In conclusion, the findings of this research underscore the potential of this novel therapeutic approach for clinical application in the treatment of recurrent gout.

Development of thermosensitive liposome-containing in-situ gel systems for intranasal administration of thiocolchicoside and in vivo evaluation in a rabbit model.

AIM: Thiocolchicoside (THC) is a drug under the category of BCS III. Due to its high molecular weight, it has poor oral bioavailability and low skin permeability. This study aims to find an alternative delivery method for THC that enhances its bioavailability through nasal application approach. In situ gels containing plain or liposomal THC with different combinations of Pluronic® F127 and PEG 400 were prepared. METHOD: Liposome formulations were prepared using the thin film hydration method and tested for their characterization such as for drug content, particle size, and zeta potential. In vivo pharmacokinetic parameters of formulations such as Cmax, Tmax, and AUC were tested on the rabbit model. The formulations were also scrutinized for their cell viability properties. RESULT: Formulation composition with 2% soybean phosphatidylcholine and 10 mg THC exhibited ∼94% entrapment efficiency, minimum particle size 101.32 nm, low polydispersity index 0.225 and +0.355 zeta potential. In situ liposomal dispersion containing 15% Pluronic® F127 turned into gel at nasal temperature. Cell lines were unharmed for 48 h. In situ liposomal gels showed 1.5x higher blood concentration than the control formula. CONCLUSION: In situ gels of liposomal THC formulations offer advantages over traditional nasal solutions, demonstrating comparable bioavailability to parenteral medication while also preserving the health of nasal mucosa cells.

[Predictive value of the product of plasma colchicine concentration and poisoning time for the prognosis of colchicine poisoning patients].

Objective: To investigate the predictive value of the product of first plasmacolchicine concentration and poisoning time for the prognosis of colchicine poisoning patients, and to provide a basis for early prognosis assessment. Methods: October 2021, patients with colchicine poisoning admitted in the First Affiliated Hospitol of Wenzhou Medical University from January 2017 to September 2021 were collected, including general information such as patient gender, age, oral colchicine dose, poisoning time, the first laboratory test index andplasma colchicine concentration after admission. The patients were divided into survival group and death group according to their prognosis. The differences in clinical indicators such as admission plasma colchicine concentration, blood routine, blood biochemistry, coagulation function, and blood gas analysis were compared between the two groups, and their predictive value for the prognosis of patients were analyzed. Results: A total of 23 patients with colchicine poisoning, aged 20-85 years, were included in this study, of which 15 cases (65.22%) survived and 8 cases (34.78%) died. The first plasma colchicine concentration at admision were 0.42-53.61 ng/ml. The plasma colchicine concentration and the concentration-time product were 10.08-2147.04 h·ng/ml.Compared with the survival group, the plasma colchicine concentration and the concentration-time product in the death group were significantly increased, and the differences were statistically significant (P<0.05). Univariate logistic regression analysis showed that first plasma concentration and poisoning time>132.48 h·ng/ml, high C-reactive protein, high D-dimer, high absolute value of BE were the risk factors for the prognosis of patients with colchicine poisoning (OR=12.000, 95%CI: 1.1181-128.836; OR=1.053, 95%CI: 1.009-1.098; OR=1.219, 95%CI: 1.039-1.429; OR=1.360, 95%CI: 1.1.044-1.773; P<0.05). High prothrombin time activity was protective factor affecting the prognosis of colchicine poisoning patients (OR=0.941, 95%CI: 0.892~0.993; P<0.05). ROC curve analysis showed that the areas under the curves of first plasma concentration and poisoning time, C-reactive protein, absolute value of BE, D-dimer for predicting the prognosis of patients with colchicine poisoning were 0.918, 0.888, 0.867, 0.837, respectively, and the areas under the curves of prothrombin time activityfor predicting the prognosis of patients with colchicine poisoning was 0.788 (P<0.05) . Conclusion: The product of the first plasma colchicine concentration at admission and poisoning time is closely related to the prognosis of patients with colchicine poisoning, it can be used as a predictor for early evaluation of the prognosis of poisoned patients.

Consensus Statement Regarding the Efficacy and Safety of Long-Term Low-Dose Colchicine in Gout and Cardiovascular Disease.

Over the last decade, evidence has demonstrated that long-term, low-dose colchicine (0.5 mg daily) is effective for preventing gout flare and cardiovascular (CV) events in a wide range of patients. Given the potentially expanding use of colchicine in CV disease, we here review and update the biologic effects and safety of colchicine based on recent data gathered from bench and pharmacodynamic studies, clinical reports, controlled clinical trials, and meta-analyses, integrated with important studies over the last 50 years, to offer a consensus perspective by experts from multiple specialties familiar with colchicine's long-term use. We conclude that the clinical benefits of colchicine in gout and CV disease achieved at low dose do not sustain serum levels above the upper limit of safety when used in patients without advanced renal or liver disease or when used concomitantly with most medications. Further, data accrued over the last 50 years strongly suggest that the biologic effects of long-term colchicine do not increase the risk of cancer, sepsis, cytopenia, or myotoxicity.

A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.

Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation.

Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.

Colchicine Inhibits Neutrophil Extracellular Trap Formation in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention.

Background Release of neutrophil extracellular traps (NETs) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) is associated with periprocedural myocardial infarction, as a result of microvascular obstruction via pro-inflammatory and prothrombotic pathways. Colchicine is a well-established anti-inflammatory agent with growing evidence to support use in patients with coronary disease. However, its effects on post-PCI NET formation in ACS have not been explored. Methods and Results Sixty patients (40 ACS; 20 stable angina pectoris) were prospectively recruited and allocated to colchicine or no treatment. Within 24 hours of treatment, serial coronary sinus blood samples were collected during PCI. Isolated neutrophils from 10 patients with ACS post-PCI and 4 healthy controls were treated in vitro with colchicine (25 nmol/L) and stimulated with either ionomycin (5 µmol/L) or phorbol 12-myristate 13-acetate (50 nmol/L). Extracellular DNA was quantified using Sytox Green and fixed cells were stained with Hoechst 3342 and anti-alpha tubulin. Baseline characteristics were similar across both treatment and control arms. Patients with ACS had higher NET release versus patients with stable angina pectoris (P<0.001), which was reduced with colchicine treatment (area under the curve: 0.58 versus 4.29; P<0.001). In vitro, colchicine suppressed unstimulated (P<0.001), phorbol 12-myristate 13-acetate-induced (P=0.009) and ionomycin-induced (P=0.002) NET formation in neutrophils isolated from patients with ACS post-PCI, but not healthy controls. Tubulin organization was impaired in neutrophils from patients with ACS but was restored by colchicine treatment. Conclusions Colchicine suppresses NET formation in patients with ACS post-PCI by restoring cytoskeletal dynamics. These findings warrant further investigation in randomized trials powered for clinical end points. Registration URL: https://anzctr.org.au; Unique identifier: ACTRN12619001231134.

Inflammation May be the Future of Cardiovascular Risk Reduction: Does Colchicine have a Current Indication?

Inflammation as a cardiovascular risk factor has attracted increasing attention . The current standard of care for decreasing the occurrence of cardiovascular events includes controlling risk factors such as hypertension and maximizing the lowering of low-density lipoprotein cholesterol (LDL-C). However, a recent study demonstrated decreased cardiovascular risk with the anti-inflammatory agent canakinumab and created more interest in decreasing cardiovascular risk by decreasing inflammation. Canakinumab is not yet approved and will undoubtedly be very expensive, so interest in an established medication such as colchicine, which is inexpensive to produce, is appropriate if evidence-based benefit is adequately confirmed. Colchicine has existing indications for gout and familial Mediterranean fever and for decreasing the incidence of postpericardiotomy syndrome. If an evidence-based benefit in decreasing cardiovascular risk can be demonstrated for colchicine, it will be of significant importance. Meta-analyses and observational studies have provided evidence to suggest that colchicine decreases cardiovascular risk because of its anti-inflammatory effects. However, randomized controlled trials (RCTs) are needed, and the recently published COLCOT (Colchicine Cardiovascular Outcomes Trial) showed definite benefit on cardiovascular outcomes in adults who had experienced a myocardial infarction within the previous 30 days. Sufficient evidence now supports the use of colchicine for secondary prevention in patients at the highest cardiovascular risk who continue to have cardiovascular events despite good blood pressure control and maximum LDL-C reduction. Nevertheless, more RCTs will be necessary before widespread general use of colchicine in cardiovascular disease prevention can be recommended. The current acquisition cost issues with colchicine also need to be resolved.

Prescription of Colchicine with Other Dangerous Concomitant Medications: A Nation-Wide Survey Using the Japanese Claims Database.

The anti-inflammatory agent colchicine may cause toxic effects such as rhabdomyolysis, pancytopenia, and acute respiratory distress syndrome in cases of overdose and when patients have renal or liver impairment. As colchicine is a substrate for CYP3A4 and P-glycoprotein (P-gp), drug-drug interactions are important factors that cause fatal colchicine-related side effects. Thus, we conducted a nation-wide survey to determine the status of inappropriate colchicine prescriptions in Japan. Patients prescribed the regular use of colchicine from April 2014 to March 2017 were identified using the Japanese large health insurance claims database. As the primary endpoint, we evaluated the concomitant prescription proportions of strong CYP3A4 and/or P-gp inhibitors classified as "contraindications for co-administration" with colchicine in patients with renal or liver impairment. We defined these cases as "inappropriate colchicine prescriptions." Additionally, factors affecting inappropriate colchicine prescriptions were analyzed. Among the 3302 enrolled patients, 43 (1.30%) were inappropriately prescribed colchicine. Of these 43 patients, 11 had baseline renal and/or liver impairment. By multiple regression analysis, the primary diseases "gout" and "Behçet's disease" were extracted as independent factors for inappropriate colchicine prescriptions with odds ratios of 0.40 (95% confidence interval: 0.19-0.84) and 4.93 (95% confidence interval: 2.12-11.5), respectively. We found that approximately 1% of patients had important colchicine interactions. Particularly, Behçet's disease was a risk factor for inappropriate prescriptions, with approximately 25% of patients showing renal and/or liver impairment (classified as "contraindications for co-administration"). These findings may be useful for medical professionals who prescribe colchicine therapy.

Simultaneous determination of colchicine and febuxostat in rat plasma: Application in a rat pharmacokinetic study.

A selective, sensitive and rapid LC-MS/MS method has been developed and validated as per US Food and Drug Administration regulatory guidelines for the simultaneous quantitation of colchicine and febuxostat in rat plasma. Colchicine and febuxostat were extracted from the rat plasma using 10% tert-butyl methyl ether in ethyl acetate using colchicine-d6 as an internal standard (IS). The chromatographic separation of colchicine, febuxostat and the IS was achieved using a mobile phase comprising 5 mm ammonium formate and 0.025% formic acid in acetonitrile (20:80, v/v) in isocratic mode on an Eclipse XDB-C18 column. The injection volume and flow rate were 5.0 µl and 0.9 ml/min, respectively. Colchicine and febuxostat were detected by positive electrospray ionization in multiple reaction monitoring mode using transition pairs (Q1 → Q3) of m/z 400.10 → 358.10 and 317.05 → 261.00, respectively. The assay was linear in the ranges of 0.25-254 and 2.60-622 ng/ml for colchicine and febuxostat, respectively. The inter- and intra-day precision values were 0.58-13.0 and 1.03-4.88% for colchicine and febuxostat, respectively. No matrix or carryover effects were observed during the validation. Both analytes were stable on the bench-top, in the autosampler and in storage (freeze-thaw cycles and long-term storage at -80°C). A pharmacokinetic study in rats was performed to show the applicability of the validated method.

Nanoengineered immunosuppressive therapeutics modulating M1/M2 macrophages into the balanced status for enhanced idiopathic pulmonary fibrosis therapy.

Effective treatment in clinic for idiopathic pulmonary fibrosis (IPF) remains a challenge due to low drug accumulation in lungs and imbalanced polarization of pro/anti-inflammatory macrophages (M1/M2 macrophages). Herein, a novel endogenous cell-targeting nanoplatform (PNCE) is developed for enhanced IPF treatment efficacy through modulating M1/M2 macrophages into the balanced status to suppress fibroblast over-activation. Notably, PNCE loaded with nintedanib (NIN) and colchicine (COL) can firstly target endogenous monocyte-derived multipotent cells (MOMCs) and then be effectively delivered into IPF lungs due to the homing ability of MOMCs, and detached sensitively from MOMCs by matrix metalloproteinases-2 (MMP-2) over-expressed in IPF lungs. After PNCE selectively accumulated within fibrosis foci, COL can mildly modulate the polarization of M1 macrophages into M2 macrophages to balance innate immune responses, which can enhance the suppressing effect of NIN on fibroblast activation, further improving the IPF therapy. Altogether, PNCE has two collaborative steps including the inhibition of innate immune responses accompanied by the decrease of fibroblast populations in IPF lungs, achieving a stronger and excellent anti-fibrotic efficacy both in vitro and in vivo. This endogenous cell-based engineered liposomal nanoplatform not only allows therapeutic drugs to take effect selectively in vivo, but also provides an alternative strategy for an enhanced curative effect by modulating innate immune responses in IPF therapy.

Different pharmaceutical preparations of colchicine for Familial Mediterranean Fever: are they the same?

This study aimed to investigate the benefit of changing the pharmaceutical preparation of colchicine in Turkish Familial Mediterranean Fever (FMF) patients resistant to one preparation in terms of frequency of the attacks. Turkish adult FMF patients under treatment with an imported colchicine preparation-in the form of compressed tablet form-due to resistance to domestic colchicine preparations, which are film- or sugar-coated tablets, and not using anti-interleukin-1 or other biologic agents were included in the study. Baseline disease characteristics along with MEFV mutations were identified. Daily colchicine doses and attack frequencies before and after the pharmaceutical change were compared. Fifty patients resistant to coated tablet preparations of colchicine and under treatment with the compressed tablets were identified. The median duration of disease was 6 (interquartile range 2.7-14) years and duration under treatment with the imported colchicine was 21 (range 8-60) months. Eight (16%), ten (20%), and 32 (64%) patients had 0-3, 4-6, and more than 7 attacks per year, respectively, before the compressed tablets. After treatment with the compressed tablet form of colchicine, 44 (88%), 5 (10%), and 1 (2%) patients had 0-3, 4-6, and more than 7 attacks, respectively (p < 0.0001). Daily colchicine doses were similar before and after the pharmaceutical change (1.85 ± 0.47 vs 1.84 ± 0.37 mg, p = 0.9). Turkish FMF patients with ongoing attacks under domestic coated tablet preparations of colchicine may benefit from the compressed colchicine tablets. This may be explained by the difference in pharmacokinetic properties of different colchicine preparations.

Studies on hepatotoxicity and toxicokinetics of colchicine.

Colchicine (COL) is an alkaloid existing in plants of Liliaceous colchicum. It has widely been used in the treatments of many diseases, such as gout, Familial Mediterranean Fever, and tumor. However, the adverse effects of COL are an obstacle to its safe use. The present studies explored the role of metabolic demethylation in the development of COL-induced hepatotoxicity. We found that inhibition of CYP3A increased the susceptibility of mice to COL hepatotoxicity, and induction of CYP3A decreased the susceptibility of animals to the hepatotoxicity. The toxicokinetic study demonstrated that pretreatment with ketoconazole caused elevated area under the concentration-time curve of COL. Three demethylation metabolites of COL were found to be less hepatotoxic than the parent compound. It appears that the formation of electrophilic demethylation metabolites was not involved in the development of COL-induced liver injury.

Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS).

INTRODUCTION: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function. METHODS AND ANALYSIS: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals. TRIAL REGISTRATION NUMBER: EUDRACT 2017-004459-21; NCT03693781; Pre-results.

Epidemiology, toxicokinetics and biomarkers after self-poisoning with Gloriosa superba.

Introduction: Gloriosa superba is a flowering plant that contains colchicine. Deliberate self-poisoning with this plant in Sri Lanka is common and potentially fatal. The objective of this study was to describe the epidemiology, toxicokinetics and selected biomarkers in these patients. Materials and methods: The study consisted of three parts; epidemiologic and outcome data (n = 297), concentrations and toxicokinetics (n = 72), evaluation of urinary and serum biomarkers (n = 45). Plasma colchicine levels were measured by high-performance liquid chromatography (HPLC). We also measured serum biomarkers: creatinine (sCr), cystatin C (sCysC) and creatine kinase (CK), and urinary biomarkers: creatinine, kidney injury molecule-1 (KIM - 1), clusterin, albumin, beta-2-microglobulin (ß2M), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN) and trefoil factor 3 (TFF3). Results: The case fatality was 10% (29/297), and death was much more common in older patients. Median concentrations of colchicine were higher in those over 65 [median 4.7 ng/mL (IQR: 1.7-6.6) vs. 1.2 (IQR: 0.2-2.7) for those <35]. Admission colchicine concentrations were highly correlated with a fatal outcome [median 7.8 ng/ml (IQR: 5.8-18.7) vs 1.2 (0-2.3) in survivors]. The area under the receiver operating characteristic curve (AUC-ROC) for uncorrected admission colchicine level was highly predictive of a fatal outcome, and this improved even further with two methods we developed to correct for the expected change with time. The best method had an AUC-ROC of 0.98 (95%CI 0.94-1.00) in predicting death, with 100% sensitivity and 96% specificity at the best cut-point. Discussion: Fatal outcomes and high concentrations were both much more common in the elderly following poisoning with Gloriosa superba. Our findings are consistent with kinetic data after medicinal colchicine ingestion. Conclusions: Gloriosa superba self-poisoning causes significant mortality. High concentration of colchicine is highly predictive of a fatal outcome. Ingestion of Gloriosa superba caused only mild acute kidney injury (AKI) and rhabdomyolysis.

The Beneficial Therapy with Colchicine for Atherosclerosis via Anti-inflammation and Decrease in Hypertriglyceridemia.

BACKGROUND: Lipid-lowering therapy and control of cardiovascular risk factors are the current recommendations of atherosclerotic disease management. Despite optimal treatment the rate of acute coronary syndrome events remains high. Inflammation plays an essential role in the pathophysiology of atherosclerotic plaque formation, progression and rupture, which conclusively causes acute clinical episodes. OBJECTIVE: This review aims to give a conceptual description of the potential therapeutic benefits and effects of colchicine in inflammation-mediated atherosclerotic disease and hypertriglyceridemia. METHOD: A complete literature survey was performed using the PubMed database search to collect available information regarding colchicine, atherosclerosis, and hypertriglyceridemia. RESULTS: A total of 42 studies met the selection criteria for inclusion in the review. Inflammation is a well-known key mediator of atherogenesis in coronary artery disease. Colchicine has direct antiinflammatory effects by inhibiting critical inflammatory signaling networks as the inflammasome, pro-inflammatory cytokines, and expression of adhesion molecules, preventing both local chemoattraction of inflammatory cells such as neutrophils and systemic inflammation including the decrease of the release of IL-1ß by the neutrophils. CONCLUSION: Colchicine reduces the levels of inflammatory markers, stabilizes the coronary plaque, leads to more favorable cardiac healing after damage, and reduces the acute coronary syndromes event recurrence. Colchicine reduces the myocardial infarct size, myocardial fibrosis, and improves the hemodynamic parameters. Several studies report the potential attenuating role of colchicine on triglyceride levels. Current evidence though regarding the pathophysiological mechanism of colchicine's triglyceride-lowering effect remains scarce.

Colchicine in Renal Diseases: Present and Future.

Colchicine is a lipophilic alkaloid drug, which exhibits ant-inflammatory and anti-fibrotic properties. Cardinal mechanisms of action of colchicine are the disruption of the microtubule system and the inhibition of neutrophil adhesion and recruitment. Colchicine is indicated in the prevention and treatment of gouty arthritis and familial Mediterranean fever. In this review, we summarize current and potentially future pharmacologic activities of colchicine in various renal disease entities along with pharmacokinetic and pharmacodynamic properties. Additionally, we will refer to main interactions of colchicine with medications used in renal medicine, as well as dosing recommendations in patients with reduced glomerular filtration rate.