Use Of Xanthine Oxidase Inhibitors Research Articles

Impact of urate-lowering therapy on the course of chronic kidney disease in patients with asymptomatic hyperuricemia: a meta-analysis of randomized controlled trials

The presented study has been carried out to identify the effect of urate-lowering therapy with xanthine oxidase inhibitors on glomerular filtration rate and serum uric acid in patients with asymptomatic hyperuricemia and chronic kidney disease. A systematic review of randomized controlled trials has been conducted; its results based on meta-analysis has been evaluated.
 A systematic search and selection of publications in Embase, PubMed, Cochrane Library, and eLibrary databases has been performed. The studied drugs were xanthine oxidase inhibitors: allopurinol and febuxostat. The study considered the following parameters such as efficacy endpoints, namely, glomerular filtration rate and serum uric acid after 3–15 months of follow-up. Clinical and methodological heterogeneity of the included randomized controlled trials has been assessed as well as publication bias and risk of systematic error. Synthesis has been performed using bivariate meta-analysis assessing residual statistical heterogeneity.
 7 selected randomized controlled trials (1203 patients) have been included in the meta-analysis. This analysis revealed that medication urate-lowering therapy (allopurinol or febuxostat) was associated with higher glomerular filtration rate (+3.0 ml/min/1.73 m2; 95% confidence interval +0.4 to +5.6; p = 0.022) compared with the controls (placebo/no urate-lowering therapy) at 3–15 months of follow-up. Along with this, medication urate-lowering therapy (allopurinol or febuxostat) has been found to result in lower serum uric acid (−3.3 mg/dl; 95% confidence interval −3.8 to −2.8; р 0.001) compared to the controls (placebo / no urate-lowering therapy) at 3–15 months of follow-up.
 The results of the meta-analysis have demonstrated a positive role of allopurinol and febuxostat in increasing glomerular filtration rate and decreasing serum uric acid in patients with chronic kidney disease and asymptomatic hyperuricemia. The presented data suggest that therapeutic measures aimed at the elimination of asymptomatic hyperuricemia, including the use of xanthine oxidase inhibitors, may be important in slowing the progression of chronic kidney failure and may be additional factors of nephroprotection.

Assessment of the In Vitro Effects of Six Selected Plant Extracts on Xanthine Oxidase

Background: Gouty arthritis is one of the most prevalent forms of arthritis caused by the deposition of uric acids mostly in joints, due to hyperuricemia. Xanthine oxidase (XO) is a key enzyme of the purine degradation pathway, catalysing the oxidation of hypoxanthine to xanthine and further to uric acid; increased activity leads to hyperuricemia hence a need to control XO activity. Commonly used therapeutic approach is the use of XO inhibitors. This study aimed to investigate if Vitis vinifera, Malus sylvestris fruit peels, Cymbopogon citratum leaves, Mucuna Pruriens leaves, Zanha africana roots and leaves, Mimosa pudica roots extracts have a Xanthine Oxidase inhibitory potential in vitro. Methodology: Air dried samples were crushed into powder using a mortar and pestle. Maceration and percolation extraction methods were used to obtain active secondary metabolites from plant materials at 10%w/v. Spectrophotometric assays methods were used for Xanthine Oxidase activity and inhibition studies. Results: The results of the current study showed that all aqueous plant extracts showed the presence of flavonoids. The experimental data showed significant inhibitory effects on XO activity. C. citratum inhibited XO activity by an average of 71%. M. sylvestris exhibited 68%, 61% and 64% at 15, 30 and 45 minutes respectively. V. vinifera exhibited 75%, 66% and 77% XO inhibitory activity at 15, 30 and 45 minutes respectively. Z. Africana exhibited 73%, 65% and 74% at 15, 30 and 45 minutes respectively. M. pudica exhibited 74%, 77% and 78% XO inhibitory activity at 15, 30 and 45 minutes respectively. M. pruriens exhibited 65%, 69% and 71% XO inhibitory activity at 15, 30 and 45 minutes respectively. Conclusion: The results obtained from the current study indicates that the flavonoids present in all plant extracts under study could be potential anti-gout agents by their inhibitory activities on Xanthine Oxidase activity

HF02-09 FATHER OF UKRAINIAN AND CZECH BIOCHEMISTRY: IVAN HORBACHEVSKY

You have accessJournal of UrologyCME1 Apr 2023HF02-09 FATHER OF UKRAINIAN AND CZECH BIOCHEMISTRY: IVAN HORBACHEVSKY Joshua Schammel and Mark White Joshua SchammelJoshua Schammel More articles by this author and Mark WhiteMark White More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003242.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Ivan Horbachevsky (May 5, 1854–May 5, 1942) was a Ukrainian pioneer in the study of biochemistry, epidemiology, and medicine. He was the first individual to synthesize uric acid in 1882 and discovered xanthine oxidase from 1889 to 1891. These discoveries have gone on to inform the urological basis for the etiology and treatment for uric acid nephrolithiasis. METHODS: A review of the literature of all aspects of Ivan Horbachevsky’s life was perfomed. RESULTS: Ivan Horbachevsky was born in Ternopil, Ukraine in 1854. He attended the University of Vienna, graduating in 1877. He conducted research through the university and was appointed as an assistant within the Institute of Medicinal Chemistry, studying medical, organic, and biological chemistry. During his time in Vienna, Horbachevsky was the first individual to synthesize uric acid from urea and glycine amino acid in 1882. As a result, he was awarded a professorship in chemistry at the Czech University in Prague in 1884. He isolated all the amino acids, proving their role as the foundation for proteins, established their synthesis and decomposition, and discovered xanthine oxidase in the late 1880s. Horbachevsky was a celebrated academician during his life. He was elected to the Royal Czech Scientific society, founded the Institute of Medical Chemistry at Charles University, and founded the Ukrainian Free University in 1919. Later in life, Horbachevsky became a champion of public health. He was elected as a member of the Czech Sanitary Council, advanced Prague’s sewer system design, and became the Austrian Minister of Health in 1918. He continued to publish and author textbooks, such as Medical Chemistry in Four Volumes 1904-8 and Organic Chemistry, 1925, until his death in 1942. In celebration for his passion for biochemistry, his groundbreaking discoveries, and contributions to medical education, the Ternopil State Medical University in Ukraine was named after Horbachevsky in 1992. CONCLUSIONS: Ivan Horbachevsky was a pioneer in biochemistry who synthesized uric acid and discovered xanthine oxidase. These discoveries would establish urologists’ knowledge of uric acid nephrolithiasis, representing 10% of all urinary calculi. These stones can be successfully dissolved by using potassium citrate and prevented through use of xanthine oxidase inhibitors. These discoveries in addition to his achievements and societal contributions have established Ivan Horbachevsky’s role as the Father of Ukrainian and Czech Biochemistry. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e253 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Schammel More articles by this author Mark White More articles by this author Expand All Advertisement PDF downloadLoading ...

HYPERURICEMIA AND ITS ASSOCIATION WITH HYPERTENSION: RISK FACTORS AND MANAGEMENT

Hyperuricemia is a medical condition that arises due to the increased concentration of uric acid in the body. Worldwide, a surge in the number of hyperuricemia cases has been seen over the last ten years. Hyperuricemia develops when the concentration of uric acid persistently crossed its normal threshold value (6 mg/dL). Uric acid is a metabolic product of purine catabolism. During the metabolism of purine, hypoxanthine is formed which is later on converted to xanthine and uric acid by the action of the xanthine oxidase enzyme. A continual increase in levels of uric acid is a major biomarker of developing gouty arthritis. Clinically, gouty arthritis is characterized by inflammation and pain in joints due to the accumulation of urate crystals in and around the affected area.1 Recently, hyperuricemia-induced renal and cardiovascular diseases have gained more consideration. Hyperuricemia is not only associated with gout but also linked with other comorbidities, including diabetes type II, heart diseases, and hypertension. A cohort study has demonstrated a threefold rise in the incidence of diabetes, hypertension, and kidney diseases in patients suffering from hyperuricemia. Epidemiological reports have revealed that factors leading to hypertension, hyperlipidemia, and obesity are commonly existed side-by-side and may considerably increase the threat of organ damage.2,3 According to estimation, 1.13 billion people around the globe are suffering from hypertension. Also, the World Health Organization has indicated that 13% of deaths happen worldwide due to hypertension and they have also set a goal of decreasing its frequency by 25% from the baseline year 2010 by the year 2025. The concept of association between blood pressure and uric acid is perhaps quite old and has been identified years ago. Multiple studies have established an independent association between uric acid and blood pressure. However, the impact of this association on direct causality is yet to be determined.4,5 In the 1870s, first time Mahomed et al had presented a hypothesis on hypertension and uric acid association. Later, Cannon et al. had conducted a study, and their research results have verified that 47% of patients were hypertensive and had elevated levels of uric acids. Previous findings have suggested that hyperuricemia participates in the pathological process of cardiovascular disorder. However, there is still no credible information is available that reveals decreasing uric acid levels will control blood pressure in adults. So far, it is not known that the use of uric acid-lowering agents will improve the condition of hypertensive patients. Xanthine oxidase inhibitors are quite effective in decreasing the serum uric acid concentration and helpful in impeding the production of reactive oxygen species (ROS). However, their potential benefit in controlling blood pressure has not been appraised and more studies are required in this regard. Hyperuricemia is linked with metabolic, renal, and cardiovascular diseases, and it is suggested that monitoring of serum uric acid is essential in hypertensive patients (blood pressure: >140/90 mmHg) and in patients who have a family history of prehypertension (blood pressure: 120–139/80–89 mmHg) with other comorbidities like obesity and diabetes. Uricosuric antihypertensive drugs (for example losartan) with diet management can be proved useful. However, diuretics should be avoided in these patients. At present, we haven’t enough evidence based on well-made clinical trials that advocate the use of xanthine oxidase inhibitors for the treatment of hypertension and above all mention their potentially harmful effects. Febuxostat can become a better alternative because it is more effective, better tolerated, and more specific than allopurinol. In this regard, long-term interventional studies are required.6 Conversely, as hypertension and hyperuricemia are linked together, a drug having antihypertensive effects might have the potential to reduce serum uric acid concentration. Traditional medicine systems can be a better option for the management and treatment of several ailments, particularly in developing countries. Currently, scientists showed more interest in natural remedies as these are safe, effective, and economical. Medicinal plants are enriched sources of various active metabolites such as flavonoids, tannins, saponins, and alkaloids that demonstrated many therapeutic activities in different studies. In the future, more experimental studies are needed to validate their usefulness and explore their possible pharmacological and toxicological effects.7,8

Xanthine oxidase inhibitors are associated with reduced risk of cardiovascular disease

As previous studies have reported finding an association between hyperuricemia and the development of cardiovascular and chronic kidney disease, hyperuricemia is thought to be an independent risk factor for hypertension and diabetic mellitus. However, we have not been able to determine whether the use of xanthine oxidase inhibitors can reduce cardiovascular disease. The present study used the longitudinal data of the Fukushima Cohort Study to investigate the relationship between the use of xanthine oxidase inhibitors and cardiovascular events in patients with cardiovascular risks. During the 3-year period between 2012 and 2014, a total of 2724 subjects were enrolled in the study and followed. A total of 2501 subjects had hypertension, diabetic mellitus, dyslipidemia, or chronic kidney disease, and were identified as having cardiovascular risks. The effects of xanthine oxidase inhibitor use on the development of cardiovascular events was evaluated in these patients using a time to event analysis. During the observational periods (median 2.7 years), the incidence of cardiovascular events was 20.7 in subjects with xanthine oxidase inhibitor and 11.2 (/1000 person-years, respectively) in those without. Although a univariate Cox regression analysis showed that the risk of cardiovascular events was significantly higher in subjects administered xanthine oxidase inhibitors (HR = 1.87, 95% CI 1.19–2.94, p = 0.007), the risk was significantly lower in subjects administered a xanthine oxidase inhibitor after adjustment for covariates (HR = 0.48, 95% CI 0.26–0.91; p = 0.024) compared to those without. Xanthine oxidase inhibitor use was associated with reduced risk of cardiovascular disease in patients with cardiovascular risk factors.

Commentaries on the updated American College of Rheumatology guidelines for the management of gout. Urate-lowering drugs (Part 1)

The emergence of updated American College of Rheumatology (ACR) guidelines for the management of gout may serve as a prerequisite for revising the draft Russian Federal Clinical Guidelines (FCGs). Despite some differences, it should be noted that both guidelines are similar in key points concerning the principles of drug correction of hyperuricemia, indications for prescription and algorithms for the use of specific medicaments. The proximity of positions can be also traced in the need for the priority use of xanthine oxidase inhibitors (allopurinol and febuxostat) for urate-lowering therapy (ULT), which is aimed at implementing the target principle of gout management – the strict, constant control of serum levels of uric acid (its value should not exceed 6 mg/dl, or 360 μmol/l). The practical results of ULT in accordance with the basic principles outlined in the FCG have been published earlier.

Febuxostat attenuates testosterone-induced benign prostatic hyperplasia in rats via inhibiting JAK/STAT axis

AimTo investigate the possible modulatory effect of febuxostat in testosterone-induced benign prostatic hyperplasia (BPH) in rats with emphasis on xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activator of transcription (STAT) axis. Main methodsMale Wistar rats were treated with testosterone with/out febuxostat. Effect of febuxostat on BPH was assessed at the structural level by histopathology and determination of prostate weight/index. Cyclin D1 protein expression was assessed immunohistochemically and the ratio of Bax/Bcl-2 mRNA expression was determined by real time polymerase chain reaction analysis (RT-PCR). Besides, uric acid serum level was determined colorimetrically. Prostatic XO activity, as well as oxidative stress and inflammatory markers were evaluated. Additionally, western blot analysis was performed for determination of JAK-1 and phosphorylated form of STAT-3 expression in tissues. Key findingsResults revealed that febuxostat inhibited the increase in prostatic weight and index compared to testosterone-treated group. Additionally, febuxostat ameliorated testosterone-induced histopathological changes, prevented the rise in cyclin D1 expression and enhanced Bax/Bcl2 ratio. Febuxostat suppressed testosterone induced- increase in XO activity in prostates and serum level of uric acid. Moreover, it regulated oxidative stress markers including; malondialdehyde (MDA), superoxide dismutase (SOD) activity and glutathione (GSH) content. Also, it inhibited the increase in prostate contents of interleukin-6 (IL-6), interleukin-1β (IL-1 β), tumor necrosis factor (TNF-α) and nuclear factor (NF-κB). Interestingly, febuxostat markedly reduced JAK-1 and subsequent phosphorylation of STAT-3 protein expression. SignificanceFebuxostat ameliorates testosterone-induced BPH via suppressing XO/JAK/STAT axis. This may help to re-purpose the use of XO inhibitors.

The effect for hyperuricemia inpatient of uric acid overproduction type or in combination with topiroxostat on the pharmacokinetics, pharmacodynamics and safety of dotinurad, a selective urate reabsorption inhibitor

BackgroundDotinurad, a novel selective urate reabsorption inhibitor (SURI), increases urinary uric acid excretion. The aim of this study is to examine the pharmacokinetics, pharmacodynamics, and safety of dotinurad according to the type of hyperuricemia, with or without concomitant use of xanthine oxidase inhibitor, in uric acid “overproduction type” patients.MethodsThis open-label clinical pharmacology study was conducted in a hospital. Dotinurad 1 mg was administered for 7 days to hyperuricemic patients with uric acid “overproduction type” (overproduction group, n = 6; and combination group, n = 6) and uric acid “underexcretion type” (underexcretion group, n = 6). In the combination group, topiroxostat 80 mg was used concomitantly.ResultsNo significant differences were observed in pharmacokinetics and safety between overproduction group and underexcretion group, and the percent change in serum uric acid level and the amount of urinary uric acid excretion after administration were comparable. In “overproduction type” patients of combination group, the percent change in serum uric acid level significantly increased and the amount of urinary uric acid excretion significantly decreased compared to those of overproduction group. No clinically meaningful differences were observed in safety between the overproduction group and the combination group.ConclusionIn inpatients, differences in hyperuricemic type did not significantly influence the pharmacokinetics, pharmacodynamics, and safety of dotinurad. Moreover, in “overproduction type”, the coadministration of dotinurad and topiroxostat had an add-on serum uric acid lowering effect and suppressed urinary uric acid excretion.Trial registrationClinicalTrials.gov Identifier: NCT02837198.

Chronic kidney disease: the role of hyperuricemia and the possibility of urate-lowering therapy

Numerous epidemiological surveys may suggest that there is a relationship between chronic kidney disease (CKD) and asymptomatic hyperuricemia; at the same time there is growing evidence that elevated uric acid (UA) is the cause of kidney injury. The possible mechanisms of CKD in hyperuricemia are said to be immune inflammation that is both mediated by UA crystallization and independent from the latter; the impact on the activity of the renin- angiotensin-aldosterone system. The currently available optimistic data on the efficiency of drug correction of hyperuricemia at different stages of CKD are justified primarily by the long-term use of xanthine oxidase inhibitors (allopurinol, febuxostat) and allow urate- lowering therapy to be regarded as potentially nephroprotective. At the same time, further large-scale randomized controlled studies are needed to confirm this finding.

Sintesis, Penilaian Biologi dan Kajian Dok Sebatian Auron ke Atas Enzim Xantin Oksidase

Inhibition of xanthine oxidase (XO) activity is an effective therapeutic approach for the treatment of diseases such as gout and hyperuricemia. Additionally, the use of XO inhibitors can further be extended to injury treatments such as ischemic reperfusion in various organs such as heart, liver and kidney. In this study, 7 aurone compounds were synthesized and tested on XO and compared with the positive control allopurinol. Compound 5e was identified as the most potent compound and was able to inhibit half of XO activity at 33.23 μM followed by compounds 5f and 5d at 210.22 μM and 302.0 μM, respectively. Finally, molecular docking study was conducted to understand the important binding interactions of the selected aurone with the active site of XO. DOI : http://dx.doi.org./10.17576/JSKM-2018-1601-17

Novel medication approved for gout

Novel medication approved for gout

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia

IntroductionGout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and...

Mendelian randomization analysis associates increased serum urate, due to genetic variation in uric acid transporters, with improved renal function

Increased serum urate predicts chronic kidney disease independent of other risk factors. The use of xanthine oxidase inhibitors coincides with improved renal function. Whether this is due to reduced serum urate or reduced production of oxidants by xanthine oxidase or another physiological mechanism remains unresolved. Here we applied Mendelian randomization, a statistical genetics approach allowing disentangling of cause and effect in the presence of potential confounding, to determine whether lowering of serum urate by genetic modulation of renal excretion benefits renal function using data from 7979 patients of the Atherosclerosis Risk in Communities and Framingham Heart studies. Mendelian randomization by the two-stage least squares method was done with serum urate as the exposure, a uric acid transporter genetic risk score as instrumental variable, and estimated glomerular filtration rate and serum creatinine as the outcomes. Increased genetic risk score was associated with significantly improved renal function in men but not in women. Analysis of individual genetic variants showed the effect size associated with serum urate did not correlate with that associated with renal function in the Mendelian randomization model. This is consistent with the possibility that the physiological action of these genetic variants in raising serum urate correlates directly with improved renal function. Further studies are required to understand the mechanism of the potential renal function protection mediated by xanthine oxidase inhibitors.

Febuxostat, an Inhibitor of Xanthine Oxidase, Suppresses Lipopolysaccharide-Induced MCP-1 Production via MAPK Phosphatase-1-Mediated Inactivation of JNK

Excess reactive oxygen species (ROS) formation can trigger various pathological conditions such as inflammation, in which xanthine oxidase (XO) is one major enzymatic source of ROS. Although XO has been reported to play essential roles in inflammatory conditions, the molecular mechanisms underlying the involvement of XO in inflammatory pathways remain unclear. Febuxostat, a selective and potent inhibitor of XO, effectively inhibits not only the generation of uric acid but also the formation of ROS. In this study, therefore, we examined the effects of febuxostat on lipopolysaccharide (LPS)-mediated inflammatory responses. Here we show that febuxostat suppresses LPS-induced MCP-1 production and mRNA expression via activating MAPK phosphatase-1 (MKP-1) which, in turn, leads to dephosphorylation and inactivation of JNK in macrophages. Moreover, these effects of febuxostat are mediated by inhibiting XO-mediated intracellular ROS production. Taken together, our data suggest that XO mediates LPS-induced phosphorylation of JNK through ROS production and MKP-1 inactivation, leading to MCP-1 production in macrophages. These studies may bring new insights into the novel role of XO in regulating inflammatory process through MAPK phosphatase, and demonstrate the potential use of XO inhibitor in modulating the inflammatory processes.

SAT0376 Uric Acid Levels as a Biomarker of Efficacy and Safety in Patients Treated with Pegloticase: Lessons Learned from us Clinical Experience

BackgroundPegloticase is a recombinant uricase recently approved in the EU for the treatment of severe, debilitating chronic tophaceous gout refractory to xanthine oxidase inhibitors (XOIs) or when XOIs are contraindicated....

THE RELATIONSHIP OF TWO XANTHINE OXIDASE SINGLE NUCLEOTIDE POLYMORPHISMS TO HYPERURICEMIA, GOUT, AND DOSE OF XANTHINE OXIDASE INHIBITOR

Background: There is evidence linking xanthine oxidase (XO) single nucleotide polymorphisms (SNPs) to multiple medical conditions. The relationship of XO SNPs to hyperuricemia/gout is limited. An in vitro study of serum from healthy adults found two XO SNPs at 2107A > G and 3662A > G associated with a two-fold higher activity of the enzyme. Materials and Methods: The main outcomes of this study were to determine if the presence of either 2107A > G or 3662A > G XO SNP led to the occurrence of hyperuricemia, gout, or necessitated a higher dose of XO inhibitor (XOI) to achieve a treatment goal of less than 6 mg/dL. A total of 72 patients were enrolled in the hyperuricemia/gout group; 41 in the control group. XO SNPs were amplified and sequenced. Patient interviews and chart reviews gathered demographic data, use of XOI, comorbidities, and serum uric acid levels. Results: The 2107A > G SNP was detected in six patients with hyperuricemia/gout and two patients in the control group. There was no association between either XO SNP with the occurrence of hyperuricemia/gout (p = 0.709). A higher dose of allopurinol was needed to achieve a treatment serum uric acid goal of less than 6 mg/dL (p = 0.049). The 3662A > G SNP was not identified in any patients in the either group of the study. Conclusion: While the presence of 2107A > G SNP had no relationship to hyperuricemia or gout in our cohort it did affect the dose of allopurinol needed to achieve a treatment goal of less than 6 mg/dL. The 3662A > G SNP was not identified in our sample.

Febuxostat, a novel drug for the treatment of hyperuricemia of gout

Febuxostat is a novel, nonpurine, selective inhibitor of xanthine oxidase (NP-SIXO), recently approved in the European Union. Febuxostat shows high, long-term efficacy for the reduction of serum urate (SU) levels, showing linear pharmacokinetics at approved doses, and its pharmacokinetics are not clinically significantly influenced by the presence of mild-to-moderate renal or liver function impairment. The clinical applicability of febuxostat should have a significant impact in patients with the highest baseline SU levels, the most severe gout, previous adverse events with other urate-lowering drugs or no availability of alternative urate-lowering drugs after failure to properly control SU levels during urate-lowering therapy. Febuxostat may become an interesting choice in our use of xanthine oxidase inhibitors.

Elevated Uric Acid Levels Predict Allograft Vasculopathy in Cardiac Transplant Recipients

Cardiac allograft vasculopathy (CAV) poses the greatest threat to the long-term survival of cardiac transplant recipients, and these individuals often exhibit elevated levels of uric acid (UA), a stimulator of T cells. We hypothesized that hyperuricemia is associated with CAV in cardiac transplant recipients. UA levels were measured in cardiac transplant recipients between January 2003 and January 2005. Surveillance cardiac catheterizations performed 3 months to 1 year after UA measurement were reviewed. The relationship between UA and CAV was adjusted for possible confounders with propensity scores and confirmed with goodness-of-fit tests. The 105 patients included in this study were a median 63.3 months post-transplant and their left heart catheterizations were performed a median 5.6 months after UA measurement. Focal stenosis was evident in 25 angiograms and 31 showed distal pruning of the coronary arteries. Compared with the lowest quartile of UA, the highest quartile had an increased risk of CAV: odds ratio (OR) 6.11 (95% CI 1.47 to 25.5; p = 0.013) for focal stenosis and OR 4.60 (95% CI 1.34 to 15.8; p = 0.015) for distal pruning. After adjustment, this relationship persisted for both focal stenosis (OR 5.53, 95% confidence interval [CI] 1.29 to 23.7; p = 0.021) and distal pruning (OR 4.21, 95% CI 1.15 to 15.4; p = 0.029). Elevated UA confers an increased risk of CAV. This association may be causal, with pathophysiologic implications for the role of hyperuricemia in allograft failure and, if substantiated, could have clinical implications for the use of xanthine oxidase inhibitors in cardiac transplant recipients.

Hyperuricemia and adverse outcomes in cardiovascular disease: potential for therapeutic intervention.

High uric acid levels are associated with increased morbidity and mortality rates in cardiovascular disease. In this article we explore the relationship between cardiovascular disease and xanthine oxidase activity. We look at the evidence that uric acid and its production via the xanthine oxidase pathway, may directly contribute to this increased cardiovascular risk. We examine the relationship between uric acid and other established cardiovascular risk factors and look at the evidence that reducing uric acid production may have a beneficial impact on cardiovascular morbidity and mortality. We conclude that although there is currently insufficient evidence to recommend the routine use of xanthine oxidase inhibitors in those with cardiovascular disease and asymptomatic hyperuricemia, there is sufficient evidence to warrant a large scale morbidity and mortality trial.

Phytochemical Investigation Of Some Traditional Chinese Medicines And Endophyte Cultures

For many social and environmental reasons, over the last few decades, there has been an increase in chronic and life-threatening diseases including mycoses, hyperuricemia-related disorders and some mental illnesses such as depression, anxiety and Parkinson’s disease. In order to fight these diseases, compounds acting on various biological targets, including enzymes such as xanthine oxidase or monoamine oxidase, have to be screened. The enzyme xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and then to uric acid, which plays a crucial role in hyperuricemiarelated disorders such as gout and renal stones. One of the therapeutic approaches to treat these diseases is the use of xanthine oxidase inhibitors that block the production of uric acid. Monoamine oxidases (E.C.1.4.3.4) A and B catalyse the oxidative deamination of monoamines in the central nervous system and peripheral tissues. Inhibitors of MAO A are clinically useful to treat anxiety and depression since they are expected to increase both noradrenalin and serotonin levels in the brain. On the other hand, inhibition of MAO B appears to be an effective approach for the prevention and adjunct treatment of Parkinson’s disease. In traditional Chinese medical practice, many medicinal herbs have been used to treat chronic diseases such as fungal infections, hyperuricemia-based disorders and mental illnesses. This usage is indicative for the presumable presence of antifungal phytochemicals and inhibitors of xanthine and monoamine oxidases. Plants do not represent the only source for interesting natural products; some endophytes (‘special’ microorganisms living inside the healthy host plant) are also known to produce secondary metabolites of promising pharmaceutical and/or agricultural potential. The above observations prompted us to search for natural antifungal compounds and inhibitors of xanthine and monoamine oxidases in different Chinese plants and endophyte cultures. The active constituents isolated were mainly mono-, sesqui-, di-, and triterpenes, sterols, coumarins, flavonoids, phenylethanoids, stilbenoids, alkaloids and alcohols.