Xanthine oxidoreductase plays an important role in formation of uric acid and its regulation during purine catabolism. Uncontrolled expression of this enzyme is responsible for overproduction and deposition of uric acid in blood that is potentially injurious because it can breakdown DNA and protein molecules, triggering many diseases. Human Xanthine oxidoreductase (HsXOR) is considered to be a pharmacological target for the treatment of hyperuricemia. Many of the HsXOR-inhibitor drugs such as Febuxostat and Allopurinol are known to have significant adverse effects. Therefore, there is an urgent need to develop new HsXOR-inhibitor drugs with less or no toxicity for the long-term treatment or prevention of hyperuricemia-related diseases. Many nutritious and medical functions have been reported in millets. Present work deals with identification of millet derived compounds in terms of their interaction with target, HsXOR through molecular docking and dynamic simulation studies. Of thirty two chosen compounds, Luteolin and Quercitin showed more binding affinity with HsXOR than reference drugs, Febuxostat and Allopurinol. Molecular dynamics simulations (20 ns long) revealed that Luteolin-protein complex was energetically more stable than Quercitin-protein complex. The millet derived compounds i.e. Luteolin and Quercitin showed binding energy -9.7 kcal/mol whereas the known drugs i.e. Febuxostat and Allopurinol showed binding energy -8.0 kcal/mol and -5.5 kcal/mol respectively. Based on the study, Luteolin possess high potential to be considered for trial as an inhibitor of HsXOR as it may regulate the pathway by inhibiting HsXOR. Further investigations are proposed to consider Luteolin for developing future drugs from millets and other natural sources.

Background -Hyperuricemia and gout are associated with increased risk of cardiovascular disease (CVD). Xanthine oxidase inhibitors (XOI), allopurinol and febuxostat, are the mainstay of urate lowering treatment for gout and may have different effects on cardiovascular risk in patients with gout. Methods -Using U.S. Medicare claims data (2008-2013), we conducted a cohort study for comparative cardiovascular safety of initiating febuxostat versus allopurinol among gout patients aged ≥65 years. The primary outcome was a composite endpoint of hospitalization for myocardial infarction (MI) or stroke. Secondary outcomes were individual endpoints of hospitalization for MI, stroke, coronary revascularization, new and recurrent heart failure (HF), and all-cause mortality. We used propensity score (PS) matching with a ratio of 1:3 to control for confounding. We estimated incidence rates (IR) and hazard ratios (HR) for primary and secondary outcomes in the PS-matched cohorts of febuxostat and allopurinol initiators. Results -We included 24,936 febuxostat initiators PS-matched to 74,808 allopurinol initiators. The median age was 76 years, 52% were male, and 12% had cardiovascular disease at baseline. The incidence rate (IR) per 100 person-years for the primary outcome was 3.43 in febuxostat and 3.36 in allopurinol initiators. HR for the primary outcome was 1.01 (95%CI 0.94-1.08) in the febuxostat compared to allopurinol groups. Risk of secondary outcomes including all-cause mortality was similar in both groups, except for a modestly decreased risk of HF exacerbation (HR 0.94, 95%CI 0.91-0.99) in febuxostat initiators. The HR for all-cause mortality associated with long-term use of febuxostat (>3 years) was 1.25 (95%CI 0.56-2.80) versus allopurinol. Subgroup and sensitivity analyses consistently showed similar cardiovascular risk in both groups. Conclusions -Among a cohort of 99,744 older Medicare patients with gout, overall there was no difference in the risk of MI, stroke, new onset HF, coronary revascularization, or all-cause mortality between patients initiating febuxostat compared with allopurinol. However, there seemed to be a trend toward an increased, albeit not statistically significant, risk for all-cause mortality in patients who used febuxostat for over 3 years versus allopurinol for over 3 years. The risk of HF exacerbation was slightly lower in febuxostat initiators.

This study investigated the synergistic effects of l-arginine and allopurinol on antioxidant and inflammatory mediators in human osteoblasts-osteoarthritis (HOb-OA) cells. The cells were treated with allopurinol (50-150 mg/kg bwt) and l-arginine (50-150 mg/kg bwt) for 72 h. Cell viability, catalase, superoxide dismutase (SOD), glutathione peroxidase (Gpx), reduced glutathione (GSH), lipid peroxidation, and the inflammatory markers interleukin 6 (IL-6), interleukin 1β (IL-1β), nuclear factor κB (NF-κB) and tumor necrosis factor alpha (TNF-α) were measured. The combined supplementation with allopurinol and l-arginine increased catalase, SOD, GSH, and Gpx, while it decreased lipid peroxidation, IL-6, IL-1β, and TNF-α. While TNF-α, IL-6, IL-1β, and NF-κB mRNA and protein expression were higher in control HOb-OA cells, the combined supplementation with allopurinol and l-arginine substantially reduced their expression in HOb-OA cells by >40%. In summary, combined supplementation with allopurinol and l-arginine might be very effective in osteoarthritis. A search for therapeutic agents that inhibit inflammation could help to prevent and manage osteoarthritis. However, further studies need to determine the biochemical and molecular mechanisms of these agents in osteoarthritis.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with CLL treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients , the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.