Piper longum L. ameliorates gout through the MAPK/PI3K-AKT pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Gout, a painful joint disease with a prevalence ranging from 0.86% to 2.2% in China over the past decade. Traditional medicine has long utilized the medicinal and edible Piper longum L. (PL) fruit spikes for treating gout and other joint conditions like rheumatoid arthritis. However, the exact mechanisms behind its effectiveness remain unclear. AIM OF THE STUDY: This study aimed to investigate the potential of alcoholic extracts from PL fruit spikes as a safe and effective treatment for gout. We used a combined network pharmacology and experimental validation approach to evaluate the mechanisms behind the anti-gout properties of PL. MATERIALS AND METHODS: UPLC-Q/TOF-MS analysis determined the major components of PL. Subsequently, network pharmacology analysis predicted potential molecular targets and related signaling pathways for the anti-gout activity of PL. Molecular docking simulations further explored the interactions between PL compounds and proteins and characterized the properties of potential bioactive secondary metabolites. Mouse models of air pouch inflammation and hyperuricemia were further established, and the anti-gout mechanism of PL was confirmed by examining the expression of proteins related to the MAPK and PI3K-AKT pathways in the tissue. RESULTS: Our analysis revealed 220 bioactive secondary metabolites within PL extracts. Network pharmacology and molecular docking results indicated that these metabolites primarily combat gout by modulating the PI3K-AKT and MAPK signaling pathways. In vivo experiments have also proven that PL at a dose of 100 mg/kg can optimally reduce acute inflammation of gout and kidney damage caused by high uric acid. The anti-gout mechanism involves the PI3K-AKT/MAPK signaling pathway and its downstream NF-κB pathway. CONCLUSION: This study provides compelling evidence for PL's therapeutic potential in gout management by modulating key inflammatory pathways. The findings offer a strong foundation for future clinical exploration of PL as a gout treatment option.

Effects of uric acid-lowering therapy (ULT) on renal outcomes in CKD patients with asymptomatic hyperuricemia: a systematic review and meta-analysis.

BACKGROUND: It is well known that asymptomatic hyperuricemia and gout play an important role in patients with chronic kidney disease (CKD). However, the effect of uric acid-lowering therapy (ULT) on the prognosis of CKD patients with asymptomatic hyperuricemia remains controversial. Therefore, we aim to investigate the influence of ULT on renal outcomes in these patients. METHODS: Comprehensive searches were conducted in PubMed, EMBASE, China National Knowledge Internet (CNKI), and the Cochrane Library, up until January 2024. We included randomized controlled trials (RCTs) that evaluated the effects of ULT on renal outcomes in CKD patients with asymptomatic hyperuricemia. RESULTS: A total of 17 studies were included in the meta-analysis. Compared with placebo or no treatment, ULT preserved the loss of estimated glomerular filtrating rate (eGFR) (Weighted mean difference [WMD] and its 95% confidence intercal(CI): 2.07 [0.15,3.98] mL/min/1.73m2) at long-term subgroup. At the same time, short-term subgroup also proved the preserved loss of eGFR (WMD 5.74[2.09, 9.39] mL/min/1.73m2). Compared with placebo or no treatment, ULT also reduced the increase in serum creatinine (Scr) at short-term (WMD -44.48[-84.03,-4.92]µmol/L) subgroup and long-term (WMD -46.13[-65.64,-26.62]µmol/L) subgroup. ULT was associated with lower incidence of the events of doubling of Scr without dialysis (relative risk (RR) 0.32 [0.21, 0.49], p < 0.001). However, no difference was found for lower incidence of acute kidney injury (AKI) (p = 0.943). CONCLUSIONS: According to our study, ULT is beneficial for slowing CKD progression both in short to long-term follow-ups. Additionally, in patients younger than 60 years old, the protective effect of ULT on renal outcome is more pronounced. However, it showed no significant difference in the incidence of AKI. These findings underscore the importance of considering ULT in clinical strategies for CKD patients with asymptomatic hyperuricemia.

Comparative studies of xanthine oxidase inhibitors viz. allopurinol and febuxostat against induced hyperuricaemia in a poultry model.

In this study, an attempt was made to evaluate the relative efficacy of two important anti-gout agents, viz. allopurinol and febuxostat, in the control of hyperuricaemia/gout using a poultry model. A 21-day study was conducted on 48 Vencobb-400 broiler chicks randomly divided into four groups. In one group hyperuricaemia/gout was induced by the oral administration of diclofenac (group D); in two other groups the ameliorative effect of the two drugs under study was investigated by providing both simultaneously, i.e. diclofenac and allopurinol (group DA), diclofenac and febuxostat (group DF); and the fourth group was kept un-induced and untreated as a control (group C). Both allopurinol and febuxostat inhibit xanthine oxidase enzymes, thereby reducing the production of uric acid. The birds kept on diclofenac alone exhibited the highest level of hyperuricaemia, clinical signs of gout, and overt adverse changes in the visceral organs, whereas these changes were lesser in allopurinol- and febuxostat-treated groups. Furthermore, haematological, biochemical, patho-morphological, and ultra-structural studies using transmission electron microscopy were carried out to evaluate the pathology and, thus, the ameliorative effect of allopurinol and febuxostat. The findings proved that allopurinol and febuxostat carry definite ameliorative potential as anti-hyperuricemic and anti-gout agents in poultry, which was better expressed by febuxostat compared to allopurinol.

Antihyperuricemic activity and inhibition mechanism of xanthine oxidase inhibitory peptides derived from whey protein by virtual screening.

Xanthine oxidase (XO), a rate-limiting enzyme in uric acid production, is the pivotal therapeutic target for gout and hyperuricemia. In this study, 57 peptides from α-lactalbumin and ß-lactoglobulin were obtained via virtual enzymatic hydrolysis, and 10 XO inhibitory peptides were virtually screened using molecular docking. Then toxicity, allergenicity, solubility, and isoelectric point of the obtained 10 novel peptides were evaluated by in silico tools. The XO activity of these synthetic peptides was tested using an in vitro assay by high-performance liquid chromatography. Their inhibitory mechanism was further explored by molecular docking. The results showed that 4 peptides GL, PM, AL, and AM exhibited higher inhibitory activity, and their half maximal inhibitory concentration in vitro was 10.20 ± 0.89, 23.82 ± 0.94, 34.49 ± 0.89, and 40.45 ± 0.92 mM, respectively. The peptides fitted well with XO through hydrogen bond, hydrophobic interaction, and van der Waals forces, and amino acid residues Glu802, Leu873, Arg880, and Pro1076 played an important role in this process. Overall, this study indicated 4 novel peptides GL, PM, AL, and AM from whey protein exhibited XO inhibitory activity, and they might be useful and safe XO inhibitors for hyperuricemia prevention and treatment.

Agents for the Treatment of Gout: Current Advances and Future Perspectives.

Gout is characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals around joints. Despite the availability of several drugs on the market, its treatment remains challenging owing to the notable side effects, such as hepatorenal toxicity and cardiovascular complications, that are associated with most existing agents. This perspective aims to summarize the current research progress in the development of antigout agents, particularly focusing on xanthine oxidase (XO) and urate anion transporter 1 (URAT1) inhibitors from a medicinal chemistry viewpoint and their preliminary structure-activity relationships (SARs). This perspective provides valuable insights and theoretical guidance to medicinal chemists for the discovery of antigout agents with novel chemical structures, better efficiency, and lower toxicity.

Emerging Urate-Lowering Drugs and Pharmacologic Treatment Strategies for Gout: A Narrative Review.

Hyperuricemia with consequent monosodium urate crystal deposition leads to gout, characterized by painful, incapacitating inflammatory arthritis flares that are also associated with increased cardiovascular event and related mortality risk. This narrative review focuses on emerging pharmacologic urate-lowering treatment (ULT) and management strategies in gout. Undertreated, gout can progress to palpable tophi and joint damage. In oral ULT clinical trials, target serum urate of < 6.0 mg/dL can be achieved in ~ 80-90% of subjects, with flare burden reduction by 1-2 years. However, real-world ULT results are far less successful, due to both singular patient nonadherence and prescriber undertreatment, particularly in primary care, where most patients are managed. Multiple dose titrations commonly needed to optimize first-line allopurinol ULT monotherapy, and substantial potential toxicities and other limitations of approved, marketed oral monotherapy ULT drugs, promote hyperuricemia undertreatment. Common gout comorbidities with associated increased mortality (e.g., moderate-severe chronic kidney disease [CKD], type 2 diabetes, hypertension, atherosclerosis, heart failure) heighten ULT treatment complexity and emphasize unmet needs for better and more rapid clinically significant outcomes, including attenuated gout flare burden. The gout drug armamentarium will be expanded by integrating sodium-glucose cotransporter-2 (SGLT2) inhibitors with uricosuric and anti-inflammatory properties as well as clinically indicated antidiabetic, nephroprotective, and/or cardioprotective effects. The broad ULT developmental pipeline is loaded with multiple uricosurics that selectively target uric acid transporter 1 (URAT1). Evolving ULT approaches include administering selected gut anaerobic purine degrading bacteria (PDB), modulating intestinal urate transport, and employing liver-targeted xanthine oxidoreductase mRNA knockdown. Last, emerging measures to decrease the immunogenicity of systemically administered recombinant uricases should simplify treatment regimens and further improve outcomes in managing the most severe gout phenotypes.

Antihyperuricemic and Renal Protective Effect of Cordyceps chanhua (Ascomycetes) Fruiting Bodies in Acute Hyperuricemia and Chronic Gout Rodent Models.

Cordyceps chanhua has been widely used in traditional Chinese medicine. The uric acid-lowering effect of artificially cultivated fruiting bodies of C. chanhua (FBCC) was studied using the acute hyperuricemia (AH) and chronic gout (CG) animal models. The AH mice and CG rats were randomly divided into 6 groups: the negative control group, model group, positive control group, low-dose group, medium-dose group, and high-dose group of FBCC, respectively. Serum uric acid, creatinine, urea nitrogen, and liver xanthine oxidase (XOD) activity were detected. Renal tubulointerstitial injury and urate crystals in CG rats were evaluated. The results showed that the uric acid content in AH mice with the high-dose FBCC group decreased statistically (P < 0.05). In the CG rats, the serum uric acid level in all FBCC groups and the serum creatinine value in the high-dose group exhibited a significant decrease (P < 0.05); the scores of renal tubulointerstitial damage and urate deposit were reduced in the high-dose group of FBCC. FBCC can reduce uric acid and improve renal function, demonstrating it as a beneficial supplement for uric acid-lowering and gout-relieving drugs.

Urate-lowering drugs for chronic kidney disease with asymptomatic hyperuricemia and hypertension: a randomized trial.

INTRODUCTION: Xanthine oxidase (XO) inhibitors may slow down chronic kidney disease (CKD) progression. The comparative effectiveness of the different urate-lowering drugs is unknown. The aim of this study was to determine whether urate-lowering therapy with an XO inhibitor (febuxostat) and that with a uricosuric drug (benzbromarone) are comparable in slowing renal function decline in patients with CKD complicated with hypertension and hyperuricemia. METHODS: This study was an open-label randomized parallel-group clinical trial of 95 patients with stage G3 CKD in Japan. The patients had hypertension and hyperuricemia without a history of gout. They were randomized to receive febuxostat ( n  = 47; febuxostat group) or benzbromarone ( n  = 48; benzbromarone group) and titrated to reduce their serum urate level to <6.0 mg/dl. The primary end-point was change in estimated glomerular filtration rate (eGFR) from baseline to 52 weeks. The secondary end-points included changes in uric acid level, blood pressure, urinary albumin-to-creatinine ratio, and XO activity. RESULTS: Of the 95 patients, 88 (92.6%) completed the trial. There were no significant differences in change in eGFR (in ml/min/1.73 m 2 ) between the febuxostat [-0.23, 95% confidence interval (CI), -2.00 to 1.55] and benzbromarone (-2.18, 95% CI, -3.84 to -0.52) groups (difference, 1.95; 95% CI, -0.48 to 4.38; P  = 0.115) nor in the secondary end-points, except for XO activity. Febuxostat significantly reduced XO activity ( P  = 0.010). There were no significant differences in primary and secondary outcomes between the groups. A decrease in eGFR was significantly less in the febuxostat group than that of the benzbromarone group in the CKDG3a, but not in CKDG3b, in the subgroup analysis. There were no adverse effects specific to either drug. CONCLUSIONS: No significant differences were found in the effects of febuxostat and benzbromarone in renal function decline in stage G3 CKD complicated with hyperuricemia and hypertension.

Model Informed Development of SIM0295 in Patients with Gout and Hyperuricemia and Healthy Volunteers Using a Population Pharmacokinetics/ Pharmacodynamics Approach.

BACKGROUND: SIM0295, a novel inhibitor of human uric acid transporter 1 (hURAT1), is used to treat patients with gout and hyperuricemia. This study aimed to develop population pharmacokinetics and pharmacodynamics (popPK/PD) models of SIM0295 and explore potential covariates to inform clinical drug development. RESEARCH DESIGN AND METHODS: Data were obtained from four phase I studies conducted in healthy Korean and Chinese subjects and two phase II studies conducted in Korean patients with gout and hyperuricemia. The popPK/PD model of SIM0295 was developed using nonlinear mixed effects modeling. RESULTS: SIM0295 pharmacokinetics was described using a two-compartment model with the absorption of four transit compartments and first-order elimination. PK parameters were normalized to weight via allometric scaling. Food was identified as a factor significantly affecting the absorption rate, with no clinical relevance. The sigmoid Emax model with a semi-mechanism of inhibition of serum uric acid (sUA) reabsorption was used to describe the exposure-response relationship. Additionally, Monte Carlo simulations demonstrated that approimately 9 mg/day of SIM0295 for 7 days could achieve the maximum decrease in sUA. CONCLUSION: The established popPK/PD model characterized the dose-exposure-response relationship for SIM0295 in healthy subjects and patients with gout and hyperuricemia and could be used to inform the drug development.

Recent advances in gout drugs.

Gout is an autoinflammatory disease caused by the deposition of urate crystals. As the most common inflammatory arthritis, gout has a high incidence and can induce various severe complications. At present, there is no effective cure method in the world. With the deepening of medical research, gout treatment drugs continue to progress. In this review, we provide a landscape view of the current state of the research on gout treatment drugs, including the research progress of anti-inflammatory and analgesic drugs, drugs that promote uric acid excretion, and drugs that inhibit uric acid production. We mainly emphasize the understanding of gout as an auto-inflammatory disease and the discovery strategy of related gout drugs to provide a systematic and theoretical basis for the new exploration of gout drug discovery.

Rapid characterisation of xanthine oxidase inhibitors from the flowers of Chrysanthemum morifolium Ramat. Using metabolomics approach.

INTRODUCTION: Hyperuricemia is the key risk factor for gout, in which the elevated uric acid is attributed to the oxidation of hypoxanthine and xanthine to uric acid by xanthine oxidase (XO). Adverse effects of the current treatments lead to an urgent need for safer and more effective alternative from natural resources. OBJECTIVE: To compare the metabolite profile of Chrysanthemum morifolium flower fraction with that of its detannified fraction in relation to XO inhibitory activity using a rapid and effective metabolomics approach. METHODS: Proton nuclear magnetic resonance (1 H-NMR)-based metabolomics approach coupled with multivariate data analysis was utilised to characterise the XO inhibitors related to the antioxidant properties, total phenolic, and total flavonoid contents of the C. morifolium dried flowers. RESULTS: The highest XO inhibitory activity, 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity, total phenolic and flavonoid content with strong positive correlation between them were observed in the ethyl acetate (EtOAc) fraction. Detannified EtOAc showed higher XO inhibitory activity than non-detannified EtOAc fraction. A total of 17 metabolites were tentatively identified, of which three namely kaempferol, 4-hydroxybenzoic acid and apigenin, could be suggested to be responsible for the strong XO inhibitory activity. Additive interaction between 4-hydroxybenzoic acid and apigenin (or kaempferol) in XO inhibition was demonstrated in the interaction assay conducted. CONCLUSION: Chrysanthemum morifolium dried flower-part could be further explored as a natural XO inhibitor for its anti-hyperuricemic potential. Metabolomics approach served as an effective classification of plant metabolites responsible for XO inhibitory activity, and demonstrated that multiple active compounds can work additively in giving combined inhibitory effects.

Angiotensin II receptor blocker and statin combination therapy associated with higher skeletal muscle index in patients with cardiovascular disease: A retrospective study.

WHAT IS KNOWN AND OBJECTIVE: Reduction in skeletal muscle mass is the most important component in diagnosing sarcopenia. Ageing and chronic heart failure due to cardiovascular diseases (CVDs) accelerate the reduction of skeletal muscles. However, there are no currently available drugs that are effective for sarcopenia. The purpose of this study was to explore the association between prescribed medications and skeletal muscle mass in patients with CVD. METHODS: This was a single-centre, retrospective, cross-sectional study. The subjects were 636 inpatients with CVD who took prescribed medicines for at least 4 weeks at the time of admission. Skeletal muscle volume was assessed using a bioelectrical impedance assay. RESULTS AND DISCUSSION: Single regression analysis showed that 10 and 3 medications were positively and negatively associated with skeletal muscle index (SMI), respectively. Stepwise multivariate regression analysis revealed that angiotensin II receptor blocker (ARB)/statin combination, dipeptidyl peptidase-4 inhibitor, and antihyperuricemic agents were positively associated with SMI while diuretics and antiarrhythmic agents were negatively associated with SMI. After adjustment using propensity score matching, the SMI was found to be significantly higher in ARB/statin combination users than in non-users. WHAT IS NEW AND CONCLUSION: Combination use of ARB/statin was associated with a higher SMI in patients with CVD. A future randomised, controlled trial is warranted to determine whether the ARB/statin combination will increase the SMI and prevent sarcopenia in patients with CVD.

Colchicine in Cardiovascular Disease: In-Depth Review.

Inflammation plays a prominent role in the development of atherosclerosis and other cardiovascular diseases, and anti-inflammatory agents may improve cardiovascular outcomes. For years, colchicine has been used as a safe and well-tolerated agent in diseases such as gout and familial Mediterranean fever. The widely available therapeutic has several anti-inflammatory effects, however, that have proven effective in a broad spectrum of cardiovascular diseases as well. It is considered standard-of-care therapy for pericarditis, and several clinical trials have evaluated its role in postoperative and postablation atrial fibrillation, postpericardiotomy syndrome, coronary artery disease, percutaneous coronary interventions, and cerebrovascular disease. We aim to summarize colchicine's pharmacodynamics and the mechanism behind its anti-inflammatory effect, outline thus far accumulated evidence on treatment with colchicine in cardiovascular disease, and present ongoing randomized clinical trials. We also emphasize real-world clinical implications that should be considered on the basis of the merits and limitations of completed trials. Altogether, colchicine's simplicity, low cost, and effectiveness may provide an important addition to other standard cardiovascular therapies. Ongoing studies will address complementary questions pertaining to the use of low-dose colchicine for the treatment of cardiovascular disease.

Design, synthesis and bioactive evaluation of geniposide derivatives for antihyperuricemic and nephroprotective effects.

Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC50 value of 6.67 ± 0.46 µM. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-κB and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage.

Network Pharmacology Study on Morus alba L. Leaves: Pivotal Functions of Bioactives on RAS Signaling Pathway and Its Associated Target Proteins against Gout.

M. alba L. is a valuable nutraceutical plant rich in potential bioactive compounds with promising anti-gouty arthritis. Here, we have explored bioactives, signaling pathways, and key proteins underlying the anti-gout activity of M. alba L. leaves for the first-time utilizing network pharmacology. Bioactives in M. alba L. leaves were detected through GC-MS (Gas Chromatography-Mass Spectrum) analysis and filtered by Lipinski's rule. Target proteins connected to the filtered compounds and gout were selected from public databases. The overlapping target proteins between bioactives-interacted target proteins and gout-targeted proteins were identified using a Venn diagram. Bioactives-Proteins interactive networking for gout was analyzed to identify potential ligand-target and visualized the rich factor on the R package via the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway on STRING. Finally, a molecular docking test (MDT) between bioactives and target proteins was analyzed via AutoDock Vina. Gene Set Enrichment Analysis (GSEA) demonstrated that mechanisms of M. alba L. leaves against gout were connected to 17 signaling pathways on 26 compounds. AKT1 (AKT Serine/Threonine Kinase 1), γ-Tocopherol, and RAS signaling pathway were selected as a hub target, a key bioactive, and a hub signaling pathway, respectively. Furthermore, three main compounds (γ-Tocopherol, 4-Dehydroxy-N-(4,5-methylenedioxy-2-nitrobenzylidene) tyramine, and Lanosterol acetate) and three key target proteins-AKT1, PRKCA, and PLA2G2A associated with the RAS signaling pathway were noted for their highest affinity on MDT. The identified three key bioactives in M. alba L. leaves might contribute to recovering gouty condition by inactivating the RAS signaling pathway.

Acute effects of hypouricemia on endothelium, oxidative stress, and arterial stiffness: A randomized, double-blind, crossover study.

We hypothesized acute moderate and drastic reductions in uric acid concentration exert different effects on arterial function in healthy normotensive and hypertensive adults. Thirty-six adults (aged 58 [55;63] years) with or without primary hypertension participated in a three-way, randomized, double-blind, crossover study in which [placebo] and [febuxostat] and [febuxostat and rasburicase] were administered. Febuxostat and rasburicase reduce the uric acid concentration by xanthine oxidoreductase inhibition and uric acid degradation into allantoin, respectively. Endothelial function was assessed in response to acetylcholine, sodium nitroprusside, heating (with and without nitric oxide synthase inhibition) using a laser Doppler imager. Arterial stiffness was determined by applanation tonometry, together with blood pressure, renin-angiotensin system activity, oxidative stress, and inflammation. Uric acid concentration was 5.1 [4.1;5.9], 1.9 [1.2;2.2] and 0.2 [0.2;0.3] mg/dL with [placebo], [febuxostat] and [febuxostat-rasburicase] treatments, respectively (p < 0.0001). Febuxostat improved endothelial response to heat particularly when nitric oxide synthase was inhibited (p < 0.05) and reduced diastolic and mean arterial pressure (p = 0.008 and 0.02, respectively). The augmentation index decreased with febuxostat (ANOVA p < 0.04). Myeloperoxidase activity profoundly decreased with febuxostat combined with rasburicase (p < 0.0001). When uric acid dropped, plasmatic antioxidant capacity markedly decreased, while superoxide dismutase activity increased (p < 0.0001). Other inflammatory and oxidant markers did not differ. Acute moderate hypouricemia encompasses minor improvements in endothelial function, blood pressure, and arterial stiffness. Clinical Trial Registration: NCT03395977, https://clinicaltrials.gov/ct2/show/NCT03395977.

Colchicine for Prevention of Atherothrombotic Events in Patients With Coronary Artery Disease: Review and Practical Approach for Clinicians.

A better understanding of the central role of inflammation in the development of coronary artery disease (CAD) has been the impetus for the evaluation of therapeutic strategies targeting the interleukin-1ß/interleukin-6 cytokine signaling pathway, involved in both chronic atherogenesis and in triggering of atherosclerotic plaque rupture. As an inexpensive pharmacologic agent with relatively few adverse effects that tend to be mild and tolerable, the role of colchicine in secondary prevention of atherothrombotic events has been the focus of multiple recent large-scale randomized controlled trials involving patients with stable CAD (Low-Dose Colchicine [LoDoCo] and LoDoCo2 trials), a recent myocardial infarction (Colchicine Cardiovascular Outcome Trial [COLCOT], Colchicine in Patients With Acute Coronary Syndrome [COPS], and Colchicine and Spironolactone in Patients With Myocardial Infarction/Synergy Stent Registry [CLEAR SYNERGY] trials), and undergoing percutaneous coronary interventions (Colchicine in Percutaneous Coronary Intervention [COLCHICINE-PCI] trial). Based on this evidence, low-dose colchicine (0.5 mg once daily) should be considered in patients with recent myocardial infarctions-within 30 days and, ideally, within 3 days-or with stable CAD to improve cardiovascular outcomes. Colchicine should not be used in patients with severe renal or hepatic disease because of the risk of severe toxicity. No serious adverse effect was associated with the combined use of colchicine and high-intensity statin therapy in large trials. The impact of colchicine in high-risk populations of patients with peripheral arterial disease and in those with diabetes for the primary prevention of CAD remains to be established.

Febuxostat reduces muscle wasting in tumor-bearing mice with LM8 osteosarcoma cells via inhibition of reactive oxygen species generation.

Cachexic condition due to malignant tumors has been a challenging problem. The aim of this study is to analyze effects of febuxostat on both in vitro and in vivo models of the wasting of skeletal muscles, due to LM8 osteosarcoma cells. C2C12 myotubes were incubated in the conditioned medium of LM8. Febuxostat was added at a concentration of 3 µM and 30 µM, and ROS, diameter of myotubes, and expression of atrogin-1 were analyzed. Furthermore, an in vivo study was performed by subcutaneous injection of LM8 on C3H mice. Febuxostat was administered in the drinking water at 5 µg/ml, and 25 µg/ml. In addition, tumor-bearing mice without febuxostat (group TB) and control mice (group C) were established. At 4 weeks, body weight, wet weights of the gastrocnemius muscles, XO activity, 8-OHdG, and expression of TNF-α and IL-6 were evaluated. ROS generation, atrophy of myotubes, and upregulation of atrogin-1 were clearly observed in C2C12 myotubes following incubation in the conditioned medium. These pathological conditions were significantly inhibited by febuxostat administration. Furthermore, mice in group TB showed significant loss of body weight and muscle weight in which XO activity, 8-OHdG, and expression of IL-6 were significantly increased compared to those in group C. Febuxostat administration not only significantly improved the body weight and muscleweight, but also reduced markers of oxidative stress and pro-inflammatory cytokines. Febuxostat did not show anti-tumor effects. Febuxostat, which is clinically used for treatment of hyperuricemia, is effective against the wasting of the skeletal muscles induced by LM8 osteosarcoma cells.

The influence of chemical composition of potent inhibitors in the hydrolyzed extracts of anti-hyperuricemic plants to their xanthine oxidase activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Anti-hyperuricemic plant parts that were selected for this study, are traditionally used to treat gout in Malaysia. Caffeic acid (a hydroxycinnamic acid), apigenin (a flavone), myricetin, quercetin and kaempferol (flavonols), were reported to act as potent xanthine oxidase inhibitors. These compounds can be found in some of the selected ethnomedicinal plants. However, there is still lack of published research works on the quantification of these inhibitors from these urate-lowering phytotherapies. AIMS OF THE STUDY: The compounds were quantified from 21 hydrolyzed extracts of the phytotherapies for gout. The activity-content contributions of the compounds to the potent extracts were determined. MATERIALS AND METHODS: The anti-hyperuricemic activities of the extracts and the compounds were determined using a xanthine oxidase inhibitory assay. Ultra-Performance Liquid Chromatography (UPLC) coupled with Photodiode Array Detector (PDA) was used to quantify the compounds in the extracts. RESULTS: The results revealed higher activity of the hydrolyzed extracts. The hydrolyzed extract of the flower bud of Syzygium aromaticum Merr. & L.M.Perry exhibited the highest activity (EC50 = 39.58 ± 0.10 µg/mL) due to the highest content of myricetin (42,297.55 ± 159.47 µg/g). The activity-content contribution of myricetin was 7.69%. Due to the highest activity of apigenin (EC50 = 3.27 ± 0.09 µg/mL), the highest contribution of this flavone (29.96%) to the hydrolyzed extract of Orthosiphon aristatus (Blume) Miq. was observed. CONCLUSION: The results revealed different contents and activities of xanthine oxidase inhibitors in the hydrolyzed extracts of anti-hyperuricemic plants can play a major role to influence the activity.