Xanthine Oxidase Inhibitors In Patients Research Articles

Analysis of appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors as the first-line urate-lowering therapy in patients with gout using the Korean Health Insurance Review and Assessment Service database.

We investigated the appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors (XOIs) as first-line urate-lowering therapy (ULT) in patients with gout. This was a nationwide population-based retrospective cohort study using the Korean Health Insurance Review and Assessment database. Patients with gout aged ≥20 years who were newly initiated on XOIs, such as allopurinol or febuxostat, from July 2015 to June 2017 and received these medications for ≥6 months were analyzed and followed up until June 2019. Persistence of XOIs was compared according to the 6-month duration of colchicine prophylaxis. For additional subgroup analysis, we also compared the persistence of XOIs according to the 3-month duration of colchicine prophylaxis. This study included 43 926 patients. The frequencies of patients with gout receiving colchicine prophylaxis for ≥6 months and ≥3 months were 6.3% and 7.6%, respectively. Allopurinol (65.2%) was prescribed more frequently than febuxostat (34.8%). During the study period, 23 475 patients (53.4%) stopped using XOIs. Colchicine prophylaxis for ≥6 months did not significantly reduce the risk of XOI discontinuation in multivariable Cox regression models. Colchicine prophylaxis for ≥3 months was significantly associated with a lower risk of non-persistence to XOIs after adjusting for confounding factors (hazard ratio = 0.95, p = .041). Our data suggest that at least 3 months of colchicine prophylaxis may be more appropriate than at least 6 months in terms of maximizing the persistence of XOIs in patients with gout.

Optimizing Thiopurine Therapy with a Xanthine Oxidase Inhibitor in Patients with Systemic Autoimmune Diseases: A Single-Centre Experience.

Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as "shunters", are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited. To investigate and describe the use of thiopurine-XOI combination therapy in shunters with systemic autoimmune diseases. Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital's laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period. Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 108 erythrocytes (p = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×108 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 108 erythrocytes (p = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg (p = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission. Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases.

Xanthine Oxidase and Transforming Growth Factor Beta-activated Kinase 1: Potential Targets for Gout Intervention.

Gout, inflammatory arthritis caused by the deposition of monosodium urate crystals into affected joints and other tissues, has become one of the major health problems of today's world. The main risk factor for gout is hyperuricemia, which may be caused by excessive or insufficient excretion of uric acid. The incidence is usually in the age group of 30- 50 years, commonly in males. In developed countries, the incidence of gout ranges from 1 to 4%. Despite effective treatments, there has been an increase in the number of cases over the past few decades. In recent years, the development of targeted drugs in gout has made significant achievements. The global impact of gout continues to increase, and as a result, the focus of disease-modifying therapies remains elusive. In addition, the characterization of available instrumental compounds is urgently needed to explore the use of novel selective and key protein-ligand interactions for the effective treatment of gout. Xanthine oxidase (XO) is a key target in gout to consider the use of XO inhibitors in patients with mild to moderate condition, however, the costs are high, and no other direct progress has been made. Despite many XO inhibitors, a selective potent inhibitor for XO is limited. Likewise, in recent years, attention has been focused on different strategies for the discovery and development of new selectivity ligands against transforming growth factor beta- activated kinase 1 (TAK1), a potential therapeutic target for gout. Therefore, the insight on human XO structure and TAK1 provides a clue into protein-ligand interactions and provides the basis for molecular modeling and structure-based drug design. In this review, we briefly introduce the clinical characteristics, the development of crystal, inhibitors, and crystal structure of XO and TAK1 protein.

Hyperuricaemia and vascular risk: the debate continues.

To update the evidence about the role of elevated levels of uric acid as a risk factor for cardiovascular disease. The review includes the most recent epidemiological evidence as well as the possible mechanisms supporting the interaction between uric acid and cardiovascular, metabolic and renal disease. The confirmed role of uric acid as involved in the onset and progression of cardiovascular and metabolic diseases. In particular, the review will focus on the possible mechanism of action of uric acid and the level of involvement of xanthine-oxidase as a mechanism responsible for both hyperuricaemia and oxidative stress. The review also briefly summarizes the most recent findings of the studies carried out with xanthine-oxidase inhibitors in patients at risk of cardiovascular disease by focusing on the possible benefits. Elevated levels of serum uric acid have been demonstrated to be closely related to the development of cardiovascular, metabolic and renal disease. The mechanism responsible for such interaction directly or indirectly involves xanthine-oxidase activation and the inflammatory system leading to structural and functional abnormalities. Preliminary results from different trials have demonstrated the favourable effects of urate-lowering treatment in the prevention of cardiovascular disease beyond the treatment of gout.

Effects of allopurinol and febuxostat on cardiovascular mortality in elderly heart failure patients.

Hyperuricemia is an emerging risk factor for the development of heart failure (HF) and is associated with a worsen prognosis of the disease. The effect of urate lowering drugs (ULT) and, in particular, the xanthine oxidase inhibitor in patients with HF is controversial. The aim of the study is to compare the effects of treatment with two different xanthine oxidase inhibitors (allopurinol or febuxostat) on cardiovascular mortality in elderly patients with chronic HF in a setting of clinical practice. In this observational trial, 255 elderly patients affected by chronic HF and treated with ULT on top of optimal medical treatment for HF. The sample included only outpatients with mild-to-moderate HF mainly secondary to chronic arterial hypertension or coronary artery disease and not previously hospitalized for HF. Patient treated with febuxostat (N. 120) and allopurinol (N. 135) were balanced for most of the baseline variables. In particular age, NYHA class distribution, drug treatment and renal function were comparable at the baseline and during the observation in both groups (p > 0.05). After a mean follow-up period of 5.1years, the cumulative cardiovascular survival was 0.96 (95% CI 0.93-0.99) in febuxostat-treated patients and 0.89 (95% CI 0.84-0.93) in those treated with allopurinol. The between group difference, adjusted for the main confounding risk factors, was statistically significant (p = 0.04). Our study results suggest that possibility that febuxostat, a selective XO inhibitor, may favorably affect cardiovascular mortality in comparison with allopurinol in elderly patients with mild-to-moderate HF. This preliminary observation deserves further evaluation in the next future.

The Role of Xanthine Oxidase Inhibitors in Patients with History of Stroke: A Systematic Review.

Xanthine oxidase inhibitors are commonly used to lower uric acid levels in patients with gout. Due to their effects on endothelial function, they have also been investigated for possible benefits for patients with cardiovascular disease. To assess the efficacy and safety of xanthine oxidase inhibitors in the treatment of patients with history of stroke. MEDLINE (1946-June 2017) and EMBASE (1947-June 2017) were queried using the search terms: "allopurinol" OR "febuxostat" OR "xanthine oxidase inhibitor" OR "xanthine oxidase/ antagonists and inhibitors" AND "stroke" OR "cerebral infarction" OR "cerebrovascular accident". Studies appropriate to the objective were evaluated, including five randomized, placebo-controlled, double-blind trials investigating the effect of allopurinol in patients with history of stroke. No articles evaluating the use of febuxostat in this setting were identified. In patients with history of stroke, treatment with allopurinol resulted in improvements in several markers of endothelial function, inflammatory markers, and scores on the Modified Rankin Scale. Study durations ranged from 6 weeks to 1 year, and studies used varying doses of allopurinol. Allopurinol was well tolerated in most studies, with some reports of gastrointestinal adverse effects, headache and rash. Based on the reviewed literature, allopurinol appears to be a promising therapy to improve vascular function and reduce disability in patients who have had a stroke. The benefits seen are in combination with current standard of care treatments with aspirin and lipid-lowering therapy. Larger trials are necessary to better understand the role of allopurinol in patients with history of stroke.

The effects of xanthine oxidase inhibitor in patients with chronic heart failure complicated with hyperuricemia: a prospective randomized controlled clinical trial of topiroxostat vs allopurinol\u2014study protocol

BackgroundHyperuricemia has a close relationship with cardiovascular diseases including heart failure. However, it is controversial whether xanthine oxidase inhibition has benefits for patients with chronic heart failure. We designed the Effect of Xanthine Oxidase Inhibitor in Chronic Heart Failure Patients Complicated with Hyperuricemia study (Excited-UA study) to compare the beneficial effects between a novel xanthine oxidoreductase inhibitor, topiroxostat, and a conventional agent, allopurinol, in patients with chronic heart failure and hyperuricemia. We focus on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level, echocardiography-based cardiac function, vascular endothelial function, renal function, inflammation, and oxidative stress.MethodsThe excited-UA is a prospective, randomized, open-label, blinded-endpoint clinical trial designed to prove our hypothesis that topiroxostat is more effective than allopurinol in patients with chronic heart failure and hyperuricemia. A total of 140 patients with chronic heart failure and hyperuricemia (plasma brain natriuretic peptide level ≥ 40 pg/mL and serum uric acid level ≥ 7.0 mg/dL) are randomly assigned (ratio 1:1) into either the topiroxostat group (40–160 mg/day) or allopurinol group (100–300 mg/day), to achieve the target uric acid level of 6.0 mg/dL. According to the protocol, all patients are followed up annually for 24 weeks. The primary endpoint is percent change in serum NT-proBNP level at 24 weeks from baseline.ConclusionsThe Excited-UA study would provide novel evidence for the clinical relevancy of xanthine oxidoreductase inhibitor treatment in patients with chronic heart failure and hyperuricemia.