Doses Of Colchicine Research Articles

CHAMOMILE (MATRICARIA CHAMOMILLA L.) EXPLORES AGRO-MORPHOLOGICAL AND GENETIC VARIATION AFFECTED BY CHEMICAL MUTAGEN

Chamomile (Matricaria chamomilla L.) is one of the most important medicinal plants in cosmetics and sanitary industries, with various applications. This research was carried out with a view to elucidate the efficacy of six doses of colchicine (0,025, 0.05, 0.1, 0.2, 0.4 and 0.8%) to improvement yield and enhance genetic diversity of chamomile mediated evaluate agronomical, chemical and molecular characteristics. Mutants with substantially superior economical properties, including number of branches, number of flowers, flower fresh and dry weight and the essential oil content, were all induced in colchicine treatments. The RAPD-PCR study has shown that the inducing mutants have been divided into two clusters. The genetic diversity coefficient has been measured at 30 and 35%. The main of two-stage polymorphism was 67.6%, and the Polymorphism Information Content (PIC) ranged between 0 to 0.449 in the bud stage and from 0 to 0.338 from in the seedling stage. Estimation of genetic diversity and selection of prefered mutants would be considerable importance in enhancement breeding programs and to identify of genotypes with higher desirable traits for further multiplication and commercial production. The usefulness of molecular markers as a method to identify the colchicine effect and meaningfully detect useful mutants was demonstrated in a combination of molecular level findings with physiological and morphological results found during various colchicine treatments. The 0.05% colchicine concentration for effective breeding of chamomile mutation is recommended in the results.

Canakinumab is effective in patients with familial Mediterranean fever resistant and intolerant to the colchicine and/or anakinra treatment.

As an autosomal recessive autoinflammatory disease, treatment of Familial Mediterranean fever (FMF) has still gaps. Clinical studies are proving the safety and efficacy of colchicine in patients with FMF. However, there are very limited data on colchicine-resistant patients treated with canakinumab. This study presents the real-life experience of two rheumatology clinics choosing canakinumab in adult patients with FMF resistant to standard therapy. Treatment-resistant FMF patients with validated diagnoses enrolled from two rheumatology clinics. A special database was generated for the study and patients' demographic characteristics, FMF attack characteristics, adverse events seen during treatment, family history, MediterraneanFeVer (MEFV) mutations, and laboratory results recorded. Patients with missing dates were excluded from the analysis. PRAS score is used to assess the disease activity. A total of thirty colchicine and/or anakinra-resistant patients were enrolled to study. Twenty-one patients were female (70%) and the average disease duration was 21years. The time from colchicine to anakinra was 4.27years and the time to canakinumab was 1.52years. Abdominal pain (100%), fever (93.3%), chest pain (56.7%) were the most prevailed findings. Morning stiffness, myalgia, low back pain, chest pain was the predominant musculoskeletal findings. Median colchicine dose was 2mg/day (min-max 0.5-3mg/day). The most common side effect during anakinra treatment, apart from treatment unresponsiveness, was injection site reactions. Before canakinumab treatment, the mean number of attacks was 8.3 in the 24weeks, 4.33 in the third month of canakinumab treatment, and 1.56 at the last visit (p < 0.001). Also, the mean duration of attacks was 67.20h before canakinumab treatment, this period decreased to 18.27h after six months of canakinumab treatment (p < 0.001). Canakinumab is effective and tolerable to reduce attacks in resistant patients with FMF. Laboratory findings and clinical observation reveals that canakinumab can be another treatment option for colchicine and/or anakinra non-responders. Further studies with larger patients are required to validate recent findings with canakinumab.

Autoinflammation leading to autoimmunity in adult-onset Still\u2019s disease: more than simple coincidence?

BackgroundAdult-onset Still’s disease (AOSD) should be considered in the differential diagnosis of patients with endocarditis, with or without a cardiac decompensation.Case presentationWe report the case of a 68-year-old Caucasian male diagnosed with AOSD after an initial acute manifestation of endocarditis with severe aortic acute manifestation of endocarditis with severe aortic insufficiency. The histological findings revealed Libman–Sacks endocarditis. He was treated with the IL-1 receptor inhibitor anakinra. Two years later the patient developed a symptomatic dilated cardiomyopathy with reduced ejection fraction (23.5%) and functional anti-beta-1-adrenergic receptor antibodies, which was initially treated with plasmapheresis; anakinra was maintained. While his AOSD symptoms responded well, our patient presented with recurrent arthritis in multiple joints, dual-energy CT showed urate deposition compatible with a gouty arthropathy. Over 7 years, he presented with recurrent episodes of arthritis and the adjustment of dosages of colchicine and febuxostat was needed. In 2018, our patient died due to a deterioration of his underlying cardiac disease.ConclusionsOnly two cases with initial endocarditis prior to AOSD diagnosis have been published, and we are not aware of any other cases reporting -β1AR-Ab development with DCM and gout in the setting of AOSD treated with anakinra.

Colchicine \u2013 an effective treatment for children with a clinical diagnosis of autoinflammatory diseases without pathogenic gene variants

BackgroundAutoinflammatory diseases (AID) are rare chronic conditions with high disease burden, affecting children and adults. Clinically and genetically confirmed, AID can be effectively treated with targeted cytokine inhibition. In contrast, for patients with clinical AID symptoms without pathogenic gene variants, no treatment recommendations are available. Colchicine is approved and established as effective, safe and low-cost first-line therapy in Familial Mediterranean Fever. Up to now, efficacy data for colchicine in children with a clinical AID diagnosis without pathogenic gene variants are rare. This pilot study was performed to evaluate the effectiveness of colchicine in children with a clinical diagnosis of AID without pathogenic gene variants.MethodsA pilot cohort study of consecutive children with active clinical AID without pathogenic gene variants treated with colchicine monotherapy was performed between 01/2009 and 12/2018. Demographics, clinical and laboratory characteristics were determined serially. Colchicine dosing and safety were documented. Physician estimate of disease activity was captured on visual analogue scales (VAS). Primary outcome: Complete response (PGA ≤2 plus CRP ≤0.5 mg/dL and/or SAA ≤10 mg/L) at last follow-up. Secondary outcomes: partial/no response, flare characteristics and requirement for rescue therapies. Analysis: Nonparametric comparison of disease activity measures.ResultsA total of 33 children were included; 39% were female. Median age at colchicine start was 3.8 years, median follow-up was 14.1 months. Clinical AID diagnoses included CAPS (24%), FMF (27%), PFAPA (43%) and unclassified AID (6%). At baseline, overall disease activity was moderate (PGA 4), inflammatory markers were elevated (CRP 12.1 mg/dL; SAA 289.2 mg/L), and 97% reported febrile flares. Outcome: 55% achieved complete response, 35% showed partial response and 58% had no febrile flares at last follow-up. Inflammatory markers (SAA: p < 0.0001, CRP: p < 0.005) and disease activity (p < 0.0001) decreased significantly. Overall, 93% of children experienced improvement of flare characteristics.ConclusionColchicine was found to be effective and safe in children with a clinical AID diagnosis in the absence of pathogenic gene variants. Colchicine is a low-cost treatment option for non-organ threatening AID.

Appendectomy history is associated with severe disease and colchicine resistance in adult familial Mediterranean fever patients

Background/aim Peritonitis attacks of Familial Mediterranean Fever (FMF) usually requires emergency medical admissions and it’s hard to distinguish a typical abdominal attack from surgical causes of acute abdomen. Therefore, history of abdominal surgery, particularly appendectomy, is very common in patients with FMF. However, history of appendectomy might also give some clues about the course of FMF in the adulthood. This study was to determine whether the history of appendectomy help to anticipate disease course of FMF in the adulthood. Materials and methods All patients recruited from FMF in Central Anatolia (FiCA) cohort, comprising 971 adult subjects. All patients fulfilled the Tel Hashomer criteria. Demographic data, FMF disease characteristics, co-morbid conditions, past medical history, surgical history and disease complications were meticulously questioned and laboratory features and genotype data (if available) were recruited from patient files. Results Appendectomy history was evident in 240 (24.7%) subjects. Disease onset was earlier and peritonitis is strikingly more prevalent (97.1% vs. 89.6%, p < 0.001) in appendectomized patients. These patients had reported almost two fold more frequent attacks in the last year compared to appendix intact patients (median 3.5 vs. 2 attacks, p = 0.001) without a difference in frequency of musculoskeletal and skin attacks. Severe disease was more common (10% vs. 5.9%, p = 0.038) due to involvement of more attack sites throughout the life and more frequent attacks. Appendectomy patients had used higher daily doses of colchicine to control disease (1.43 ± 0.6 mg vs. 1.27 ± 0.52 mg, p = 0.002) but colchicine resistance was also more common in these patients, 15% vs. 6.7% respectively, p < 0.001.ConclusionAppendectomy history is common in FMF patients and associated with frequent serositis attacks in adulthood. These patients require higher colchicine doses with a lower rate of response and more need for Interleukin-1 antagonist therapies.

Phenotypic characterization of Familial Mediterranean Fever patients harboring variants of uncertain significance

Background/aimFamilial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations on the MEFV gene located on the short arm of chromosome 16. Although some MEFV variants are clearly associated with disease phenotype, there are numerous variants with unknown clinical association which are termed as variants of uncertain significance (VUS). Here, we present clinical correlations of VUS in a large cohort of adult FMF patients from three tertiary centers located in Central Anatolia.Materials and methodsAll patients were recruited from FMF in Central Anatolia (FiCA) cohort. Demographic (sex, age at disease onset) and clinical features (disease characteristics, attack frequency, mean colchicine dose, colchicine nonresponsiveness, amyloidosis, and persistent inflammation) of patients with VUS were compared with those harboring pathogenic variants. Disease severity and damage were also evaluated using international severity score for FMF (ISSF) and autoinflammatory disease damage index (ADDI), respectively.ResultsAmong 971 participants included, MEFV gene analysis results were available for 814 patients. Twenty-six (3.2%) patients had single heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variants. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with single heterozygous pathogenic variant (p > 0.05 for all). No difference was observed in the demographic and clinical features of patients with single heterozygous pathogenic mutation and pathogenic/VUS complex heterozygous variant (p > 0.05 for all). ISSF and ADDI scores were lower in pathogenic/VUS complex heterozygous patients than those harboring single pathogenic mutation (p = 0.006 and 0.004, respectively).ConclusionOur findings suggest that patients with single heterozygous VUS has mild FMF phenotype similar to those with single pathogenic mutation. Pathogenic/VUS complex heterozygosity does not lead to a more severe clinical phenotype than having a single pathogenic variant.

Anti-inflammatory mechanisms and research progress of colchicine in atherosclerotic therapy.

Inflammatory responses play a vital role in the onset and development of atherosclerosis, and throughout the entire process of the chronic disease. The inflammatory responses in atherosclerosis are mainly mediated by the NLRP3 inflammasome and its downstream inflammatory factors. As a powerful anti‐inflammatory medicine, colchicine has a history of more than 200 years in clinical application and is the first‐choice treatment for immune diseases such as gout and familial Mediterranean fever. In atherosclerosis, colchicine can inhibit the assembly and activation of NLRP3 inflammasome via various mechanisms to effectively reduce the expression of inflammatory factors, thereby reducing the inflammation. Recent clinical trials show that a low dose of colchicine (0.5 mg per day) has a certain protective effect in stable angina patients or those with acute myocardial infarction after PCI. This article summarizes and discusses the mechanisms of colchicine in the treatment of atherosclerosis and the latest research progress.

Impact of urate-lowering therapy on quality of life indicators in patients with gout

Gout can have a significant impact on the quality of life (QoL) of patients.Objective: to assess the dynamics of QoL indicators and the possibility of achieving the target level of uric acid (UA) in patients with gout on febuxostat therapy, with ineffectiveness and / or contraindications to the allopurinol administration.Patients and methods. The prospective, single-center study included 80 patients with gout. The follow-up period was at least 6 months of allopurinol or febuxostat (Azurix®) therapy in doses required to achieve the target UA level. When urate-lowering therapy was initiated, allopurinol 100 mg per day was prescribed, followed by dose titration (up to maximum of 900 mg per day) until the target UA level was reached (&lt;360 μmol/L). Patients with ineffectiveness of allopurinol and / or adverse reactions (ADRs) were transferred to febuxostat 80–120 mg per day. To prevent arthritis attacks, all patients received low doses of non-steroidal anti-inflammatory drugs or colchicine 0.5 mg per day or glucocorticoids 7,5 mg per day (in prednisolone equivqlent). At the first and last visits, patients on febuxostat completed the SF-36 questionnaire.Results and discussion. After 6 months of follow-up, 70 (88%) patients received urate-lowering therapy, of whom 51 (73%) reached the target UA level. Allopurinol dosage titration required 26 patients, of whom 14 (54%) achieved the treatment goal. Due to the ineffectiveness of allopurinol, 32 patients were switched to febuxostat, which allowed to achieve normouricemia in 69% of cases. Fifteen (68%) of 22 patients who were initiated with febuxostat due to ADRs to allopurinol also achieved the target UA level. Patients who received febuxostat and reached the target UA level improved QoL indicators: role-physical functioning, bodily pain, general health, vitality and general physical well-being (p&lt;0.05 in all cases). Patients who did not reach the target UA level on febuxostat therapy improved such indicators as physical functioning, role-physical functioning, and bodily pain (p&lt;0.05 in all cases). High compliance was observed in 63% of patients, treated with febuxostat and in 36% of patients, treated with allopurinol.Conclusion. In patients with ineffectiveness or intolerance to allopurinol, in 69% of cases febuxostat allows to achieve the target UA level and improving QoL and complience.

Colchicine and the heart.

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

Persistence of disease flares is associated with an inadequate colchicine dose in familial Mediterranean fever: A national multicenter longitudinal study

Familial Mediterranean fever (FMF) is characterized by self-limited episodes of fever and polyserositis.1 MEFV gene encodes for a protein named Pyrin, which plays a pivotal role in the activation and secretion of IL-1.2 Daily colchicine is highly effective in preventing attacks in this disorder in a dose-related fashion.3 Many definitions of colchicine resistance are available in the literature. The European League Against Rheumatism (EULAR) guidelines defined resistance as one or more attacks per month in compliant patients who had been receiving the maximally tolerated dose for at least 6 months.

Does Familial Mediterranean Fever Provoke Atherosclerosis in Children? Evaluation of Arterial Stiffness and Serum Endocan Levels.

This study aimed to evaluate the risk for atherosclerosis by using echocardiographic arterial stiffness (AS) parameters and serum endocan levels, as a biomarker of endothelial dysfunction (ED) in children with FMF. Seventy-nine children with FMF (12-18 years) and 41 healthy children were included, and clinical features (age at the first attack, age at the time of diagnosis, diagnosis delay time, colchicine dose, biological agent usage, MEFV mutations, and symptoms of attacks) of patients were noted. Arterial stiffness parameters were calculated by using echocardiographic aortic measurements with blood pressure monitoring. Hemogram parameters, acute phase reactants, blood glucose and lipid levels of 12 hours of fasting, and serum endocan levels were evaluated for all participants. There were no statistically significance regarding demographic features, acute phase reactants, and hemogram parameters. Blood glucose and lipid levels were similar, except for HDL (lower in FMF group, p=0.029). Serum endocan levels did not differ in two groups (p=0.906). Only stiffness of descending aorta was lower in FMF group (p=0.028), and the other AS parameters were similar between two groups (p>0.05 for each parameters). Good disease control could be preventive for atherosclerosis in children with FMF. On the other hand, screening for cardiovascular diseases is essential, particularly for uncontrolled cases. Distribution of MEFV gene mutations KEY POINTS: • Exaggerated inflammation is the prominent feature of FMF attacks; moreover, it is shown that subclinical inflammation might also continue in attack-free periods. • Chronic inflammation contributes to atherosclerotic process in almost all stages by activating endothelial cells, producing reactive oxygen species, and accelerating foam cell and atherosclerotic plaque formations. • However, the results of this study showed that there was no difference in terms of atherosclerotic markers such as serum endocan levels and arterial stiffness parameters between pediatric FMF patients and healthy peers. • Good disease control in pediatric FMF patients may prevent early atherosclerotic changes during childhood, which then may lead a probable decreased risk of subsequent CVD in adulthood.

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.

Efficacy of anti-interleukin-1 treatment in colchicine-resistant arthritis in patients with familial Mediterranean fever.

In the familial Mediterranean fever (FMF) clinic, arthritis is among the most common symptoms, and it generally responds well to colchicine treatment. However, cases of patients with chronic prolonged colchicine-resistant arthritis have been reported, and there are inadequate studies on the treatments to be used for such patients. This study included 18 patients diagnosed with FMF who had colchicine-resistant chronic arthritis and received anti-interleukin (IL)-1 treatment for at least 1 year. The clinical and laboratory data of the patients were retrospectively retrieved from the database of our hospital. Remission was achieved in arthritis attacks in 16 of 18 patients who started anti-IL-1 therapy because of colchicine-resistant chronic arthritis. The clinical and laboratory values of the other 2 patients improved, but complete remission could not be achieved. The treatment dose of colchicine was reduced with anti-IL-1 therapy. In addition to the improvement in arthritis symptoms, remission was achieved in other clinical findings of FMF by anti-IL-1 therapy. In this study, with an average follow-up time of 33 months, no adverse effects requiring discontinuation were observed in any patient. Anti-IL-1 therapy is effective and reliable in the treatment of colchicine-resistant chronic FMF arthritis. The efficacy of anti-IL-1 therapy was realized without concomitant disease-modifying antirheumatic drug therapy, despite the reduction in colchicine dose.

Optimization of chromosome doubling treatment for efficient in vivo doubled haploid production in maize

Abstract An investigation to optimize the protocol for application of colchicine for enhancing the doubled haploid production in maize was done. 106 maize genotypes were used as maternal parents, whereas, pollen source involved tropically adopted haploid inducer (TAIL P1 and TAIL hybrid). After the elimination of chromosomes of inducer lines, haploid seeds were obtained from the crosses. Haploid seedlings were treated with three different doses, such as 0.04, 0.06 and 0.08 per cent of colchicines for different durations (8, 12 and 15 hours). The response of various colchicine concentrations applied for different time durations revealed significant differences at P ≤ 0.05 for various parameters viz., per cent plants survivability, stalk colour, the fertility of tassel, silk present/absent, pollen viability, seed set and per cent doubled haploid formation. In maize, colchicine doses of 0.04 per cent for 12 hours and 0.06 per cent for 8 hours, respectively were established as optimum for enhanced doubled haploid production. But among these two, 0.04 per cent for 12 hours was observed to be best dose for doubled haploid production in maize.

Clinical Implications of S100A12 and Resolvin D1 Serum Levels, and Related Genes in Children with Familial Mediterranean Fever

AbstractThe aim of this article was to study the role of S100A12 and resolvin D1-related genes and serum levels in the diagnosis and detection of subclinical inflammation in children with familial Mediterranean fever (FMF) during the quiescent stage of the disease. Seventy-eight children with FMF during the silent state and 60 healthy control were studied. Serum S100A12 and resolvin D1 were quantitatively measured using enzyme-linked immunosorbent assay. In addition, the levels of C-reactive protein, erythrocyte sedimentation rate, and hemoglobin were determined. The clinical severity was evaluated. The link between the Mediterranean fever (MEFV) gene and the genes related to the two studied biomarkers was also assessed. Correlation between S100A12 and resolvin D1 and the clinical severity was assessed. The mean serum levels of S100A12 and resolvin D1 were 847.4 and 793.3, respectively, which were highly significantly increased (p = 0.001) compared with the controls (324.3 and 235.1, respectively). The receiver operating characteristic curve test showed that S100A12 had a sensitivity of 97.4% and specificity of 80% with cutoff value of 529.5, while resolvin D1 showed a sensitivity of 100% and specificity of 50% with cutoff value of 231.2. A correlation was detected between the clinical severity and S100A12 and resolvin D1. This study delineated that S100A12 and resolvin D1 are sensitive biomarkers to detect the degree of inflammation in children with FMF during the silent period. Consequently, we recommend adjusting the colchicine dose to ameliorate the disease's symptoms and to improve the quality of life in these patients.

Does Age at Onset Affect the Clinical Presentation of Familial Mediterranean Fever in Children?

The aim of this study was to compare the clinical and demographic features and evaluate the phenotypic and genotypic differences of pediatric familial Mediterranean fever (FMF) patients according to their age at disease onset. Records of 854 patients who were diagnosed with FMF between 2006 and 2017 were evaluated. Patients were divided into 2 subgroups according to their age at disease onset. Group 1 comprised FMF patients who had experienced their first attack at 2 years or younger (younger onset), and group 2 comprised FMF patients who had experienced their first attack at older than 2 years. There were 155 patients in group 1 and 699 patients in group 2. Delay in diagnosis, attack frequency, duration of attacks, fever, chest pain, erysipelas-like erythema, incidence of family history, anti-interleukin 1 therapy use, and M694V homozygous and M680I homozygous mutations were significantly higher in group 1, whereas arthralgia and abdominal pain were significantly higher in group 2. There were no significant differences in arthritis, amyloidosis, and protracted febrile myalgia between the groups. The colchicine dose at last visit and Pras activity score were higher in group 1. It seems that FMF patients with a younger onset has a more severe disease course. They needed higher doses of colchicine to control the attacks. M694V and M680I homozygous mutations presented more frequently in younger-onset FMF patients. Increased awareness of physicians of the early presentation of FMF may prevent delays in FMF diagnosis.

Colchicine as an Adjuvant Therapy for Coronary Artery Disease: A Systematic Review

Background:Inflammation plays a significant role in atherosclerosis at all phases. Colchicine is a pleiotropic anti-inflammatory agent that may be beneficial in various stages of coronary artery disease (CAD).&#x0D; Methods:We searched for literatures in PubMed, Cochrane Library, ScienceDirect, and Proquest regarding the use of colchicine on top of current optimal medical therapy for CAD.&#x0D; Results: Twelve studies were identified: three studies in stable CAD patients and the remaining nine assessed in acute coronary syndrome (ACS) and post-ACS patients. The majority of studies used a colchicine dose of 0.5 mg/day. Adjuvant colchicine of 0.5 mg daily reduced the risk of developing ACS, cardiac arrest, or ischemic stroke in stable CAD: HR (hazard risk) 0.33 (95% CI 0.18-0.59), p&lt;0.001. Patients admitted with ACS who received a 2 mg loading dose of colchicine pre-percutaneous coronary intervention (PCI) showed smaller infarct size than control: 18.3 (IQR 7.6-29.9) ml/1.73 m2vs 23.2 (18.5-33.4) ml/1.73 m2(p=0.019).In post-ACS patients, adjuvant colchicine of 0.5 mg daily significantly reduced the rate of ischemic cardiovascular events: HR 0.77 (95% CI 0.61-0.96), p=0.02.&#x0D; Conclusion: Stable CAD patients benefit from 0.5 mg daily dose of adjuvant colchicine to reduce the incidence of future cardiovascular events. For patients presenting with ACS, a loading dose of 2 mg of colchicine pre-PCI followed by a week of 0.5 mg colchicine twice daily on top of optimal medical care can reduce infarct size. This should be followed by consumption of 0.5 mg daily dose of adjuvant colchicine post-ACS for at least 20 months to prevent future reinfarctions.

Analysis of polymorphisms in the colchicine binding site of tubulin in colchicine-resistant familial Mediterranean fever patients.

Familial Mediterranean fever is a hereditary autoinflammatory syndrome. The typical treatment for the disease is colchicine. However, a subset of patients are not responsive to colchicine. In this study, polymorphisms in the colchicine-binding site of the TUBB1 gene, which encodes a tubulin isoform specific to leukocytes, were investigated in patients with colchicine-resistant disease. FMF patients who were followed in the Department of Pediatric Rheumatology at Hacettepe University were included in this study. Colchicine resistance was defined as ongoing disease activity (≥ 1 attack/month over 3months or persistently elevated CRP) while taking the maximum tolerated dose of colchicine. A total of 62 Turkish FMF patients (42 colchicine-responsive and 20 colchicine-resistant) and a control group of healthy children were included in the study. DNA was extracted for analysis of TUBB1, and the colchicine binding site was sequenced. We did not observe A248T (rs148237574) or M257V (rs759579888), two variations that were previously associated with colchicine resistance in an in silico analysis. We did detect T274M (rs35565630), R306H (rs772479017), and R307H (rs6070697) variants in the FMF patients, but there was no statistically significant difference between the colchicine-responsive and colchicine-resistant groups. This is the first study to evaluate TUBB1 gene polymorphisms in the colchicine binding site in patients with FMF. Our data do not support the hypothesis that these polymorphisms are a possible cause of colchicine resistance in FMF patients.

Efficacy of Xixiancao (Herba Siegesbeckiae Orientalis) on interactions between nuclear factor kappa-B and inflammatory cytokines in inflammatory reactions of rat synovial cells induced by sodium urate.

To investigate the interaction between nuclear factor kappa-B (NF-κB) and inflammatory cytokines in synovial cell inflammatory responses induced by sodium urate, and to evaluate the efficacy of Xixiancao (Herba Siegesbeckiae Orientalis) on these interactions. The interactions between NF-κB and inflammatory cytokines/mediators in synovial cells in acute gouty arthritis were investigated. We observed the expressions of NF-κB, interleukin (IL)-1β, IL-8, and tumor necrosis factor alpha (TNF-α) in synovial cells at different timepoints in an in vitro model of synovial cell inflammatory responses induced by sodium urate and in an in vivo model of gouty arthritis. Changes in the expressions of NF-κB, IL-1β, IL-8, and TNF- in synovial cells of all experimental groups were compared and observed after treatment with different doses of Xixiancao (Herba Siegesbeckiae Orientalis) and colchicine. The interactions between NF-κB and IL-1β, IL-8, and TNF-α were analyzed. Pathological changes in synovial tissues were observed in rats with acute gouty arthritis. Compared with the blank group, the expression levels of NF-κB, IL-1β, IL-8, and TNF-α were increased significantly at different timepoints in the in vitro model of synovial cell inflammatory responses induced by sodium urate, and in the in vivo model of gouty arthritis. Compared with the model group, the expressions of NF-κB, IL-1β, IL-8, and TNF-α in synovial cells induced by sodium urate were decreased in the different Xixiancao (Herba Siegesbeckiae Orientalis) dose groups and the colchicine group. The effect was more obvious in the high dose Xixiancao (Herba Siegesbeckiae Orientalis) group. The expression of NF-κB in synovial cells was positively correlated with the expressions of IL-1β, IL-8, and TNF-. Histopathological examination of synovial tissues in the high dose Xixiancao (Herba Siegesbeckiae Orientalis) group and Colchicine group showed that the characteristics of acute gouty arthritis were reduced, and there was a trend towards a positive correlation between NF-κB and inflammatory cytokine expressions. The activation of NF-κB is associated with the activation of IL-1β, IL-8, and TNF-α during the pathogenesis of acute gouty arthritis, leading to the continuation and enhancement of the inflammatory response. Expressions of IL-1β, IL-8, and TNF-α in synoviocytes during acute gouty arthritis effectively inhibit local inflammation.

Colchicine increases intestinal permeability, suppresses inflammatory responses, and alters gut microbiota in mice

Although colchicine (COL) has been used to treat gout for more than a thousand years, it has been shrouded in a dark history for a long time due to its high toxicity, especially for the gastrointestinal tract. With the widespread clinical application of COL, COL’s toxicity to the gastrointestinal tract has raised concerns. This study’s objective was to address the exact intestinal toxicity of COL, with particular attention to the effects of COL on gut microbiota homeostasis. The mice were exposed to various dosages of COL (0.1, 0.5, and 2.5 mg kg−1 body weight per day) for a week, and the results showed that COL exposure caused serious intestinal injuries, reducing the relative expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and tight junction proteins (zo-1, claudin-1, and occludin) in the ileum and colon tissue. The 16S rRNA gene sequencing analysis of mice feces samples revealed that the composition and diversity of intestinal microbiome underwent a profound remodeling at the dosage of 2.5 mg kg−1 body weight per day, which may increase the toxic load in the gut. In addition, elevated levels of diamine oxidase (DAO) and lipopolysaccharide (LPS) in serum indicated that COL increased intestinal permeability, impairing intestinal barrier. In conclusion, our results demonstrate that COL’s toxicity to the gut microbiome is compatible with intestinal injuries, inflammatory pathway inhibition, and increased intestinal permeability; our results also represent a novel insight to uncover the adverse reactions of COL in the gastrointestinal tract.