Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Xanthine oxidase inhibitors (XOI), classified as purine-like (allopurinol and oxypurinol) and non-purine (febuxostat and topiroxostat) XOI, present antioxidant properties by reducing the production of reactive oxygen species derived from purine metabolism. Oxidative stress is an important factor related to endothelial dysfunction and ischemia-reperfusion injury, and may be implicated in the pathogenesis of heart failure, hypertension, and ischemic heart disease. However, there is contradictory evidence regarding the possible cardiovascular (CV) protective effect exerted by XOI. Our objective is to compare the incidence of major adverse cardiovascular events (MACE), mortality, total (TCE) and specific CV events in randomized controlled trials (RCTs) testing XOI against placebo or no treatment. METHODS: PubMed, EMBASE, Web of Science, Cochrane Central, Lilacs databases were searched from inception to Dec 30 2016, along with hand searching. RCTs including exclusively adult individuals, lasting ≥ 4 weeks, with no language restriction, were eligible. Independent paired researchers selected studies and extracted data. Considering the expected rarity of events, Peto and DerSimonian/Laird odds ratios (OR), the latter in case of heterogeneity, were used for analysis. Random-effects meta-regression was used to explore heterogeneity. RESULTS: The analysis of MACE included 81 articles (10,684 patients, 6434 patient-years). XOI did not significantly reduce risk of MACE (ORP = 0.71, 95% CI 0.46-1.09) and death (0.89, 0.59-1.33), but reduced risk of TCE (0.60, 0.44-0.82; serious TCE: 0.64, 0.46 to 0.89), and hypertension (0.54, 0.37 to 0.80). There was protection for MACE in patients with previous ischemic events (0.42, 0.23-0.76). Allopurinol protected for myocardial infarction (0.38, 0.17-0.83), hypertension (0.32, 0.18-0.58), TCE (0.48, 0.31 to 0.75, I2 = 55%) and serious TCE (0.56, 0.36 to 0.86, I2 = 44%). Meta-regression associated increasing dose of allopurinol with higher risk of TCE and serious TCE (P < 0.05). Accordingly, lower doses (≤ 300 mg/day) of allopurinol reduced the risk of TCE, unlike higher doses. Non-purine-like XOI did not significantly reduce or increase the risk of adverse CV events, but confidence intervals were wide. Quality of evidence was generally low to moderate. CONCLUSIONS: Purine-like XOI may reduce the incidence of adverse CV outcomes. However, higher doses of allopurinol (> 300 mg/day) may be associated with loss of CV protection.

Latent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti-tumor necrosis factor agents.

The introduction of biological agents, especially the tumor necrosis factor inhibitors (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI) is strongly recommended before starting therapy with anti-TNF agents. The objective of this study was to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF agents. This is a cross-sectional study. The electronic medical records of all adult patients (≥18 years old) undergoing anti-TNF treatment were reviewed. Every patient underwent tuberculin skin test (TST) before starting anti-TNF treatment. In total, 176 patients were included; the mean age was 51.9 ± 12.4 years, 34.7% were males, and 90.9% were white. The underlying diseases were rheumatoid arthritis (RA) in 50.6% (N = 89), ankylosing spondylitis (AS) in 27.8% (N = 49), and psoriatic arthritis (PsA) in 17.6% (N = 31). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p = 0.020). RA patients had lower TST reactions than AS patients (p = 0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR's recommendation that patients who live in high TB incidence settings should be tested annually for LTBI.

Incidence of tuberculosis infection in spondyloarthritis patients treated with biological and conventional disease-modifying anti-rheumatic drugs in an endemic area

Introduction: Registries of spondyloarthritis (SpA) patients' follow-up provided evidence that tumor necrosis factor inhibitors (TNFi) increase the incidence of active tuberculosis infection (TB). However, most of these registries are from low burden TB areas. Few studies evaluated the safety of biologic agents in TB endemic areas. This study compares the TB incidence rate (TB IR) in anti-TNF-naïve and anti-TNF-experienced subjects with SpA in a high TB incidence setting.Methods: In this retrospective cohort study, medical records from patients attending a SpA clinic during 13 years (2004 to 2016) in a university hospital were reviewed. The TB IR was calculated and expressed as number of events per 105 patients/year; the incidence rate ratio (IRR) associated with the use of TNFi was calculated.Results: A total of 277 patients, 173 anti-TNF-naïve and 104 anti-TNF-experienced subjects, were evaluated; 35.7% (N = 35) of patients who were prescribed an anti-TNF drug were diagnosed with latent tuberculosis infection (LTBI). Total follow-up time (person-years) was 1667.8 for anti-TNF-naïve and 394.9 for anti-TNF-experienced patients. TB IR (95% CI) was 299.8 (37.4-562.2) for anti-TNF naïve and 1012.9 (25.3-2000.5) for anti-TNF experienced subjects. The IRR associated with the use of TNFi was 10.4 (2.3- 47.9).Conclusions: In this high TB incidence setting, SpA patients exposed to anti-TNF therapy had a higher incidence of TB compared to anti-TNF-naïve subjects, although the TB incidence in the control group was significant.(AU)

In vitro effects of L-arginine and guanidino compounds on NTPDase1 and 5'-nucleotidase activities from rat brain synaptosomes.

Tissue accumulation of arginine (Arg), N-acetylarginine (NA), argininic acid (AA) and homoarginine (HA) occurs in hyperargininemia, an inborn error of the urea cycle. In the present study, we investigated the in vitro effects of Arg, NA, AA and HA on NTPDase1 and 5'-nucleotidase activities from synaptosomal cerebral cortex of rats. The results showed that Arg enhances NTPDase1 activity at the high concentrations tested (1.5 and 3.0mM) for both the ATP and ADP nucleotides. Activation was also observed with other guanidino compounds tested: NA, AA and HA activated ATP and ADP hydrolysis in all experiments at the concentration of 25 microM. Besides this, NA and AA activated ATP hydrolysis at a lower concentration (1 microM). In another set of experiments, we verified the effect of Arg on purified apyrase at pH 8.0 and 6.5 and observed an increase in the enzyme activity at all Arg concentrations tested (0.01-3.0mM). In contrast, Arg and the other guanidino compounds tested did not alter 5'-nucleotidase activity. These results suggest that changes in nucleotide hydrolysis may be involved in the brain dysfunction caused by hyperargininemia amongst other potential pathophysiological mechanisms involved in this condition.

Enhanced NTPDase and 5'-nucleotidase activities in diabetes mellitus and iron-overload model.

The activity of the enzymes NTPDase and 5'-nucleotidase was studied in both diabetes mellitus and an associated model of iron-overload. Rats were divided in five groups: citrate (CC), saline (S), diabetic (D), iron-overload (IO), and diabetic iron-overload (DIO). Diabetes was induced with alloxan (150 mg/kg), and iron-overload was induced with iron-dextran (10 intramuscular applications of +/-80 mg/kg). The enzymatic activities were evaluated in the platelets. The results demonstrated an increase in the activity of NTPDase with substrates ATP and ADP (60% and 120%, respectively; P<0.001), and 5'-nucleotidase (60%, P<0.001). This increase was more intense in the IO and DIO groups. The results obtained in vitro showed an activation in ATP, ADP, and AMP hydrolysis between 1 microM and 1,000 microM ferric nitrate concentrations, being more pronounced at 100 microM and decreasing at 1,000 microM. We concluded that diabetes mellitus in association with iron-overload increased the hydrolysis of adenine nucleotides in platelets, contributing to the abnormalities found in these pathological conditions.