Rational Design of Colchicine Derivatives as anti-HIV Agents via QSAR and Molecular Docking.

BACKGROUND: Human immunodeficiency virus (HIV) is an infective agent that causes an acquired immunodeficiency syndrome (AIDS). Therefore, the rational design of inhibitors for preventing the progression of the disease is required. OBJECTIVE: This study aims to construct quantitative structure-activity relationship (QSAR) models, molecular docking and newly rational design of colchicine and derivatives with anti-HIV activity. METHODS: A data set of 24 colchicine and derivatives with anti-HIV activity were employed to develop the QSAR models using machine learning methods (e.g. multiple linear regression (MLR), artificial neural network (ANN) and support vector machine (SVM)), and to study a molecular docking. RESULTS: The significant descriptors relating to the anti-HIV activity included JGI2, Mor24u, Gm and R8p+ descriptors. The predictive performance of the models gave acceptable statistical qualities as observed by correlation coefficient (Q2) and root mean square error (RMSE) of leave-one out cross-validation (LOO-CV) and external sets. Particularly, the ANN method outperformed MLR and SVM methods that displayed LOO-CV 2 Q and RMSELOO-CV of 0.7548 and 0.5735 for LOOCV set, and Ext 2 Q of 0.8553 and RMSEExt of 0.6999 for external validation. In addition, the molecular docking of virus-entry molecule (gp120 envelope glycoprotein) revealed the key interacting residues of the protein (cellular receptor, CD4) and the site-moiety preferences of colchicine derivatives as HIV entry inhibitors for binding to HIV structure. Furthermore, newly rational design of colchicine derivatives using informative QSAR and molecular docking was proposed. CONCLUSION: These findings serve as a guideline for the rational drug design as well as potential development of novel anti-HIV agents.

Colchicine in Post-operative Atrial Fibrillation: A Review.

Post-operative atrial fibrillation (POAF) is a frequent entity increasing hospitalization duration, stroke and mortality. In the recent years, a few studies have sought to investigate the potential effect of colchicine in POAF prevention after cardiac surgery or catheter pulmonary vein isolation for AF. In the present review article, we intend to provide a synopsis of clinical practice guidelines, summarize and critically approach current evidence for or against colchicine as a means of POAF prevention.

The therapeutic effect of quercetin on gouty arthritis and its influence in renal function in rats / 天津医药

Objective To investigate the therapeutic effect of quercetin on acute gouty arthritis and its influence in re-nal function in rats. Methods Seventy male Sprague-Dawley rats were randomly divided into normal control group, model group, colchicine group (0.5 mg/kg), allopurinol group (20 mg/kg), quercetin 100, 200 and 400 mg/kg groups (n=10 for each group). Rats were administered various drugs by oral gavage once a day for seven consecutive days throughout the experi-ment. On the fifth day, the animal model of acute arthritis was set up by giving monosodium urate crystal combined with hypo-xanthine. The inflammatory reaction was detected by measuring the circumference of right hind leg anklejoint with a tie line method at 0, 2, 6, 12, 24 and 48 h. The swelling ratio was calculated. The serum levels of uric acid (UA),β2-microglobulin (β2-MG), cystatin C (Cys-C), urea nitrogen (Urea) and creatinine (Cr) were detected by colorimetry and enzyme-linked im-munosorbent assay.Rats were sacrificed at the end of experiment, and the kidney was weighed and the renal index was calcu-lated. Results Treatment with quercetin, colchicine or allopurinol can significantly attenuate swelling rate in rats of acute gouty arthritis. The serum levels of UA were significantly higher in colchicine group and quercetin group than those of nor-mal control group and allopurinol group. The serum levels of UA was significantly lower in allopurinol group than that of nor-mal control group. After 48-h modeling, there was no significant difference in serum UA level between seven groups except allopurinol group. The levels ofβ2-MG and Cys-C were the lowest in normal control group than those of other groups. The se-rum levels of Urea and Cr and renal index were the highest in allopurinol group compared with those of other groups ( P<0.05). Conclusion Quercetin shows a significant effect of anti-inflammatory on acute gouty arthritis in rats. The model es-tablishment may lead to different degrees of renal damage. Quercetin has no protective effect against renal injury, and allopu-rinol aggravates kidney injury.

Application of improved chromosome short-term culture method in the chromosome karyotype analysis of leukemia patients / 西安交通大学学报(医学版)

Objective To make the chromosome karyotype analysis of 130 patients with leukemia by using the improved chromosome short-term culture method.Methods We optimized the main factors with a single factor gradient experiment in short-term culture of bone marrow chromosome, including colchicines concentration, duration of action of colchicines,and hypotonic time.On this basis,we conducted the three-factors and three-level orthogonal experiment to achieve improved bone marrow chromosome preparation system,which was later applied in 130 patients with leukemia in our hospital.Results The orthogonal experiment results showed that the optimum conditions were colchicines concentration of 0.07 μg/mL,colchicines action time of 80 min,and hypotonic time of 35 min during the preparation of the bone marrow chromosome.Using this method,the chromosome preparation success rate reached 97.69% and the detection rate of abnormal karyotype reached 82.3% in the chromosome karyotype analysis.Conclusion Bone marrow chromosome preparation system with colchicines concentration of 0.07 μg/mL and colchicines action time of 80 min,and hypotonic time of 35 min is worthy of clinical promotion.

Colchicine--Update on mechanisms of action and therapeutic uses.

OBJECTIVES: To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. METHODS: We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. RESULTS: The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. CONCLUSION: Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions.

Synthesis and characterization of a PAMAM dendrimer nanocarrier functionalized by SRL peptide for targeted gene delivery to the brain.

Blood-brain barrier inhibits most of drugs and genetic materials from reaching the brain. So, developing high efficiency carriers for gene and drug delivery to the brain, is the challenging area in pharmaceutical sciences. This investigation aimed to target DNA to brain using Serine-Arginine-Leucine (SRL) functionalized PAMAM dendrimers as a novel gene delivery system. The SRL peptide was linked on G4 PAMAM dendrimers using bifunctional PEG. DNA was then loaded in these functionalized nanoparticles and their physicochemical properties and cellular uptake/distribution evaluated by AFM, NMR, FTIR and fluorescence and confocal microscopy. Also, biodistribution and brain localization of nanoparticles were studied after IV injection of nanoparticles into rat tail. Unmodified nanoparticles were used as control in all evaluations. In vitro studies showed that SRL-modified nanoparticles have good transfection efficacy and low toxicity. Results also showed that SRL is a LRP ligand and SRL-modified nanoparticles internalized by clathrin/caveolin energy-dependent endocytosis to brain capillary endothelial cells. After intravenous administration, the SRL-modified nanoparticles were able to cross the blood-brain barrier and enter the brain parenchyma. Our result showed that, SRL-modified nanoparticles provide a safe and effective nanocarrier for brain gene delivery.

Association between colchicine resistance and vitamin D in familial Mediterranean fever.

Although colchicines are the only effective treatment of familial Mediterranean fever (FMF), resistance to colchicines (CR) which is observed in up to 30% of the patients is still a problem. Clinically, resistance to colchicine is defined as three or more attacks within the last 6 months period while using ≥2 mg/day colchicine. Previous studies have shown decreased vitamin D levels in FMF patients compared with healthy controls. The aim of this study is to evaluate whether vitamin D levels differ between CR and non-CR FMF patients. This study included 64 FMF patients who were being followed in Nephrology Clinic of Samsun Research and Education Hospital for at least 1 year. FMF was diagnosed according to the criteria defined by Livneh et al. Serum 25-hydroxy vitamin D (25-OHD) concentration (ng/mL) was detected in all FMF patients who were not in an acute attack period. From 64 patients 29 were accepted as CR. Mean 25-OHD level was 9.39 ± 1.00 ng/mL in CR patients and 18.48 ± 1.09 ng/mL in colchicine responsive patients (p < 0.001). Plasma vitamin D levels were significantly lower in colchicine resistant patients. Vitamin D deficiency may be a factor in etiopathogenesis of CR. Studies in larger patient samples that particularly evaluate the response to vitamin D replacement in CR FMF patients are needed.

Therapeutic efficacy of small doses of colchicine combined with glucocorticoid for acute gouty arthritis / 解放军医学杂志

Objective To observe the clinical effect of small dose of colchicine combined with glucocorticoid for acute gouty arthritis. Methods Ninety-two patients with acute gouty arthritis were equally and randomly divided into small doses of colchicine combined with dexamethasone treatment group (treatment group) and conventional large dose colchicine treatment group (control group) between January 2009 and December 2013. The articular lesion scoring and clinical efficacy evaluation were performed at 3, 6, 12, 24, 48, and 72h after treatment. Erythrocyte sedimentation rate (ESR), white blood cells, hepatorenal function and glomerular filtration rate (GFR) were determined before and 72h after treatment respectively. The gastrointestinal adverse events and recurrence rate were observed within one month after treatment. Results The articular lesion scores were significantly decreased at 6, 12, 48, and 72h after treatment in treatment group compared with control group (P0.05). Serum uric acid, glutamic-pyruvic transaminase in serum (SGPT), and GFR did not show any change before and 72h after the treatment, and there was also no significant difference between groups (P>0.05). The incidence of gastrointestinal adverse events were obviously higher in control group (76.1%) compared with that of the treatment group (P<0.05), and the differences was statistically significant. There was no statistical difference in recurrence rate between the control group and treatment group after a follow-up of one month. Conclusions Compared with conventional large dose colchicine, small dose of colchicine combined with dexamethasone can more rapidly and effectively control acute gouty arthritis, with good tolerability and safety, thus being worthy of popularization clinically.

Clinical application of ultraviolet spectrophotometric method in detection of colchicine poisoning serum / 国际检验医学杂志

Objective To explore the application of the ultraviolet spectrophotometry method in detecting colchicine poisoning serum to provide the basis for clinical diagnosis and treatment of colchicine poisoning.Methods 0.5 mL of serum was taken and added with the extract solution(chloroform∶methanol=95 ∶5)4.0 mL.The sufficient oscillation extraction and high-speed cen-trifugation were performed.Then the organic layer was taken into another test tube for drying by nitrogen.0.2 mL of methanol dis-solved residue was taken and blended.50 μL of the mixed solution was taken for conducting ultraviolet scanning.Results The max-imum absorption peak of serum colchicine was (351 ±1)nm,the concentration within 5.0-40 μg/mL showed linearity,the regres-sion equation wasY =0.050 2X +0.001 3,the correlation coefficient was 0.999 5,the recovery rate was 83.8% -102.8%,the rel-ative standard deviation:3.3% -4.8%.The intra-day and inter-day were 3.22%-4.74% and 3.45%-4.66%,the lowest detec-tion concentration was 1 .0 μg/mL.Conclusion This method is simple to operate,fast in analysis,accurate in the detection result, which provides a simple and accurate detection method for clinical diagnosis of colchicine poisoning.

New cytotoxic benzosuberene analogs. Synthesis, molecular modeling and biological evaluation.

In this Letter we describe the synthesis and biological evaluation of new benzosuberene analogs with structural modifications on the B-ring. The focus was initially to probe the chemical space around the B-ring C-8 position. This position was readily available for derivatization chemistry using our recently developed new synthesis for this compound class. Furthermore, we describe two new B-ring analogs, one containing a diene and the other a cyclic ether group. Both new analogs show excellent potencies in tumor cell proliferation assays. In addition, we describe molecular modeling studies that provide a binding rationale for reference compound 8 in the colchicine binding site using the known colchicine crystal structure. We also examine whether the cell based potency data obtained with selected new analogs are supported by modeling results.

Targeting the unstable plaque in acute coronary syndromes.

BACKGROUND: Rupture or erosion of an unstable atherosclerotic plaque is the typical pathology and usual cause of acute coronary syndromes. Despite detailed understanding of the processes of lipid accumulation, thinning of the fibrous cap, and inflammation leading to plaque instability, there are no strategies in clinical use that uniquely target the unstable plaque. OBJECTIVE: A critical review of recent publications on potential therapies that could be used to stabilize unstable plaque. METHODS: We searched PubMed, other literature databases, drug development sites, and clinical trial registries to retrieve clinical studies on anti-inflammatory and lipid-modulating therapies that could be used to stabilize unstable atherosclerotic plaque. RESULTS: Multiple experimental targets involving lipid and inflammatory pathways have the potential to stabilize the plaque and expand the armamentarium against coronary artery disease. Randomized clinical trials of darapladib, methotrexate, canakinumab, and colchicine are well advanced to establish if plaque stabilization is feasible and effective in patients with acute coronary syndromes. CONCLUSIONS: Although there are still no agents in clinical use for plaque stabilization, there are important advances in understanding plaque instability and several encouraging approaches are being evaluated in Phase III clinical trials.

Clinical characteristics of amyloidosis with isolated respiratory system involvement: A review of 13 cases.

BACKGROUND: Isolated pulmonary amyloidosis is a very rare disease. METHODS: We retrospectively reviewed the records of patients with pathologically proven isolated pulmonary amyloidosis treated at our hospital from 1990 to 2011. RESULTS: There were 9 males and 4 females with a mean age of 54.7 years (range, 45-72 years) and the mean course of disease was 46.5 months (range, 5 months-15 years). The most common symptoms were cough (10/13), expectoration (8/13), hemoptysis (4/13), chest tightness (12/13), dyspnea (10/13), chest pain (3/13), fever (5/13), and body weight loss (2/13). Radiological findings included tracheal stenosis (2/13), bronchial stenosis with atelectasis (5/13), pulmonary nodules (3/13), lung consolidation (1/13), and lymph node enlargement with pleural effusion (2/13). Treatments included endotracheal stenting, endoscopic resection of tracheal and bronchial lesions, lung resection, and drug therapy with glucocorticoids, antineoplastic agents, or antibiotics. Four patients died of the disease within 1 year of diagnosis, 2 died of pneumonia at 3-4 years after original treatment, and the remaining patients are alive with follow-up ranging from 3 to 15 years. CONCLUSIONS: Isolated pulmonary amyloidosis is a rare disease with a relatively high mortality and its various manifestations make diagnosis challenging. Surgical resection of lesions and chemotherapy tend to be effective treatments.

Tissue culture and generation of autotetraploid plants of Sophora flavescens Aiton.

BACKGROUND: Sophora flavescens Aiton is an important medicinal plant in China. Early in vitro researches of S. flavescens were focused on callus induction and cell suspension culture, only a few were concerned with in vitro multiplication. OBJECTIVE: To establish and optimize the rapid propagation technology of S. flavescens and to generate and characterize polyploid plants of S. flavescens. MATERIALS AND METHODS: The different concentrations of 6-benzylaminopurine (BAP), indole-3-acetic acid (IAA) and kinetin (KT) were used to establish and screen the optimal rapid propagation technology of S. flavescens by orthogonal test; 0.2% colchicine solution was used to induce polyploid plants and the induced buds were identified by root-tip chromosome determination and stomatal apparatus observation. RESULTS: A large number of buds could be induced directly from epicotyl and hypocotyl explants on the Murashige and Skoog medium (MS; 1962) supplemented with 1.4-1.6 mg/l 6-benzylaminopurine (BAP) and 0.3 mg/l indole-3-acetic acid (IAA). More than 50 lines of autotetraploid plants were obtained. The chromosome number of the autotetraploid plantlet was 2n = 4× = 36. All tetraploid plants showed typical polyploid characteristics. CONCLUSION: Obtained autotetraploid lines will be of important genetic and breeding value and can be used for further selection and plant breeding.

Clinical Observation on Pagosid in the Treatment of Acute Gouty Arthritis / 中国药房

OBJECTIVE:To observe the therapeutic effect of pagosid in treating acute gouty arthritis.METHODS:70pa-tients were randomly assigned to treatment with pagosid(treatment group)or colchicine(control group),the onset time of therapeutic effect,symptom amelioration,blood uric acid descending level and adverse drug reactions of the two groups were monitored.RESULTS:There were ameliorated clinical symptoms in both groups;however,the blood uric acid level of the treatment group were reduced,and little adverse reaction involved in this group and the onset of curative effects was slow,which stood at(65.78?30.19)hours.CONCLUSION:Treatment of acute gouty arthritis with pagosid ameliorates hyper-uricemia and mitigates pain and swelling accepted by patients better.

Quadruple Thera py of Behcet's Disease

Behcet's disease is a multisystematic inflammatory disorder affecting eyes. Visual loss is the most serious effect of Behcet's disease with posterior segment involvement.Because of the disorder's devastating visual consequences, its treatment has received considerable attention.Since the treatment of Behcet's disease has often been unsatisfactory, many different types of treatment have been attempted. We retrospectively reviewed the charts of 28 patients with severe ocular Behcet's disease involving posterior segment.The patients with posterior segment involvement were initially treated with triple regimen (corticosteroid, colchicines, and azathioprine).If intraocular inflammation does not resolve or the inflammatory process recurs, combination with low doses of cyclosporine should be considered (quadruple therapy).Over the course of therapy, visual acuity improved in 25 of 51 eyes (49.01%), remained stable in 14 of 51 eyes (27.45%), and declined in 12 of 51 eyes (23.52%).It improved or maintained the visual acuity in 39 of 51 eyes.There were no serious side effects attributable to triple or quadruple therapy that required withdrawal. The use of corticosteroids, colchicines, azathioprine, and cyclosporine may improve therapeutic efficacy and limit the adverse drug effects, and this combination method appears to be an effective treatment for the ocular complications of Behcet's disease.