allopurinol and Chronic-Disease

Calcium stones are common and recurrent in nature, yet few therapeutic tools are available for secondary prevention. Personalized approaches for stone prevention have been informed by 24-hour urine testing to guide dietary and medical interventions. However, current evidence is conflicting about whether an approach guided by 24-hour urine testing is more effective than a generic one. The available medications for stone prevention, namely thiazide diuretics, alkali, and allopurinol, are not always prescribed consistently, dosed correctly, or tolerated well by patients. New treatments on the horizon hold the promise of preventing calcium oxalate stones by degrading oxalate in the gut, reprogramming the gut microbiome to reduce oxalate absorption, or knocking down expression of enzymes involved in hepatic oxalate production. New treatments are also needed to target Randall's plaque, the root cause of calcium stone formation.

Topics: Alkalies; Allopurinol; Body Fluids; Calcium; Chronic Disease; Humans; Oxalates

This review aims to critically present the available clinical evidence supporting the treatment of chronic hyperuricemia with xanthine oxidase inhibitors. For this reason, the studies published on uric acid (UA)-lowering drugs in the English language from 2000 to August 2019 have been carefully reviewed. The terms "serum uric acid," "xanthine oxidase," "allopurinol," "febuxostat," and "topiroxostat" were incorporated into an electronic search strategy, alone and in combinations, in both MEDLINE (National Library of Medicine, Bethesda, MD) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). Even if new urate-lowering drugs seem of particular efficacy for acute treatment of refractory hyperuricemia, their use is supported by relatively small clinical evidence. On the contrary, large long-term clinical trials have demonstrated that xanthine oxidase inhibitors (XOIs, namely, allopurinol and febuxostat) are effective, safe, and relatively well-tolerated in most of the patients. They have mainly been tested in the elderly, in patients affected by chronic diseases such as heart failure and cancer, and in patients taking a large number of drugs, confirming their safety profile. Recent data also show that they could exert some positive effects on vascular health, renal function, and glucose metabolism. Their cost is also low. In conclusion, XOIs remain the first choice of UA-lowering drug for chronic treatment.

Topics: Allopurinol; Benzaldehydes; Chronic Disease; Comorbidity; Febuxostat; Gout Suppressants; Humans; Hyperuricemia; Nitriles; Pyridines; Randomized Controlled Trials as Topic; Xanthine Oxidase

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.

Topics: Acetamides; Allopurinol; Benzbromarone; Chronic Disease; Evidence-Based Medicine; Febuxostat; Gout Suppressants; Humans; Hyperuricemia; Naphthalenes; Nitriles; Phenylacetates; Polyethylene Glycols; Probenecid; Propionates; Pyridines; Thioglycolates; Triazoles; Urate Oxidase; Uricosuric Agents; Xanthine Oxidase

Gout is an increasingly common chronic disorder of urate crystal deposition that manifests as flares of acute inflammatory arthritis. Hyperuricaemia is a prerequisite and a fifth of both men and woman are hyperuricaemic. The prevalence of gout is much lower than the prevalence of hyperuricaemia for reasons that are not currently clear. Gout is more common in men than women prior to menopause due to the uricosuric effects of oestrogen, but after menopause the incidence of gout rises substantially in women. Co-morbidities are an important issue in gout, with cardiovascular disease, diabetes mellitus, obesity and chronic kidney disease all common in patients with gout. Environmental factors like diet affect the incidence of gout but there is little evidence to support an emphasis on diet in treating established gout. The diagnosis of gout is often made without the use of joint aspiration and validated diagnostic rules are available for both primary and secondary care as well as classification criteria for research use. The overarching principle of the management of gout with pharmacotherapy is the need to reduce serum urate levels to below a target of 0.30 mmol/L or 0.36 mmol/L depending on whether it is tophaceous or non-tophaceous respectively. The use of allopurinol has been researched extensively and newer strategies for safer effective dosing are now recommended. Newer agents have been introduced for the treatment of gout, including febuxostat and lesinurad. A number of important questions in the field are under current investigation.

Topics: Allopurinol; Chronic Disease; Comorbidity; Diet; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Probenecid; Thioglycolates; Triazoles; Uric Acid

To determine if urate-lowering treatment (ULT) in gout can reduce cardiovascular (CV) outcomes.. Randomized trials were searched for treatment with ULT in gout. Eligible trials had to report CV safety of a ULT. Potential medications included allopurinol, febuxostat, pegloticase, rasburicase, probenecid, benzbromarone, sulphinpyrazone, losartan, fenofibrate and sodium-glucose linked transporter 2 inhibitors.. A total of 3084 citations were found, with 642 duplicates. After the primary screen, 35 studies were selected for review. Several trials did not report CV events. Six were not randomized controlled trials (RCTs). Four studies reported no events in either intervention arm while the other four had 40 events in the febuxostat group ( n = 3631) and 5 in allopurinol group ( n = 1154). Overall, the pooled analysis did not show a significant difference between the two [febuxostat vs allopurinol: relative risk (RR) 1.69 (95% CI 0.54, 5.34), P = 0.37]. CV events did not decrease over time. Comparing shorter studies (<52 weeks) to longer ones did not reveal any statistical differences. However, in long-term studies with febuxostat vs allopurinol, results were nearly significant, with more CVE occurring with febuxostat treatment. Comparing any ULT to placebo (eight studies, n = 2221 patients) did not demonstrate a significant difference in non-Anti-Platelet Trialists' Collaboration events [any ULT vs placebo: RR 1.47 (95% CI 0.49, 4.40), P = 0.49] or all-cause mortality [any ULT vs placebo: RR 1.45 (95% CI 0.35, 5.77), P = 0.60].. RCT data do not suggest differences in CV events among ULTs in gout. Trials had few events despite high-risk patients being enrolled and may have been too short to show CV reduction by controlling inflammatory attacks and lowering uric acid.

Topics: Adult; Allopurinol; Arthritis, Gouty; Cardiovascular Diseases; Chronic Disease; Febuxostat; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Polyethylene Glycols; Prognosis; Randomized Controlled Trials as Topic; Treatment Outcome; Urate Oxidase

Several studies suggest that chronic hyperuricemia, the main precursor of gout, is involved in the pathogenesis of different systemic disorders that affect cardiovascular and renal systems, such as hypertension, obesity, hypercholesterolemia, atherosclerosis, metabolic syndrome, chronic heart failure, and chronic kidney disease. Recent epidemiological evidence has shown an increasing trend in the prevalence of hyperuricemia and gout in the Western world: a number of population-based studies estimate a prevalence of up to 21% for hyperuricemia and 1%-4% for gout. As such, early detection and careful management of this pathological condition is required, starting from lifestyle changes (mainly based on a diet low in red meat, sugars, and alcoholic beverages, with increased intake of vegetables, water, and vitamin C sources), adding specific drugs to lead serum uric acid (SUA) levels under the target value of 7 mg/dL. In particular, nonselective and selective XO inhibitors (allopurinol, oxypurinol, febuxostat) reduce SUA levels and the overproduction of reactive oxygen species, mainly related to XO overactivity that often causes inflammatory damage to the vascular endothelium. The effect of lowering SUA levels via XO inhibition includes an attenuation of oxidative stress and related endothelial dysfunction that largely contribute to the pathophysiology of metabolic syndrome and cardiovascular diseases. Therefore, the inhibition of XO overactivation seems to be an excellent therapeutic option to limit the harmful effects of excess UA and reactive oxygen species. In conclusion, rapid diagnosis and correct therapy for hyperuricemia may also improve the prevention and/or treatment of serious and multifactorial diseases. The available evidence supports the importance of promoting new experimental clinical trials to confirm the emerging antioxidant role of XO inhibitors, which could effectively contribute to cardiovascular and chronic kidney disease prevention.

Topics: Antioxidants; Biomarkers; Chronic Disease; Down-Regulation; Enzyme Inhibitors; Evidence-Based Medicine; Humans; Hyperuricemia; Oxidative Stress; Treatment Outcome; Uric Acid; Xanthine Oxidase

Topics: Allopurinol; Arthritis, Gouty; Chronic Disease; Diet Therapy; Female; Gout; Health Care Costs; Humans; Incidence; Male; Needs Assessment; Patient Care Planning; Prognosis; Risk Assessment

Chronic wounds are an important health problem because they are difficult to heal and treatment is often complicated, lengthy and expensive. For a majority of sufferers the most common outcomes are long-term immobility, infection and prolonged hospitalisation. There is therefore an urgent need for effective therapeutics that will enhance ulcer healing and patient quality of life, and will reduce healthcare costs. Studies in our laboratory have revealed elevated levels of purine catabolites in wound fluid from patients with venous leg ulcers. In particular, we have discovered that uric acid is elevated in wound fluid, with higher concentrations correlating with increased wound severity. We have also revealed a corresponding depletion in uric acid precursors, including adenosine. Further, we have revealed that xanthine oxidoreductase, the enzyme that catalyses the production of uric acid, is present at elevated levels in wound fluid. Taken together, these findings provide evidence that xanthine oxidoreductase may have a function in the formation or persistence of chronic wounds. Here we describe the potential function of xanthine oxidoreductase and uric acid accumulation in the wound site, and the effect of xanthine oxidoreductase in potentiating the inflammatory response.

Topics: Allopurinol; Chronic Disease; Enzyme Inhibitors; Free Radical Scavengers; Free Radicals; Humans; Inflammation; Uric Acid; Varicose Ulcer; Wound Healing; Xanthine Dehydrogenase

Gout is currently one of the most common causes of inflammatory arthritis in most industrialised countries. Apart from its high frequency, gout is associated with disability, poor quality of life and increased mortality and therefore represents an ever increasing public health concern. Substantial experimental and epidemiological evidence exists supporting the link between elevated levels of serum uric acid and several comorbidities including cardiovascular and kidney diseases. The cornerstone of effective gout management is long-term serum urate lowering below saturation concentrations (<6 mg/dL or <360 μmol/L) in order to promote crystal dissolution and prevent monosodium urate crystals formation. The management of gout includes not only pharmacological approaches, but also a number of nonpharmacologic interventions aiming at lessening attack risk, lowering uric acid levels and promoting general health while preventing the development of comorbidities. It is of great address whether urate lowering strategies can also lower cardiovascular risk and some preliminary studies in both animal and human subjects suggest that they might. Patient education and appropriate lifestyle advice are core aspects of management of hyperuricemia and gout. The two xanthine oxidase inhibitors currently available are effective as long-term urate lowering therapy although the greater efficacy and good tolerability of febuxostat as urate lowering agent has to be adequately considered especially when the reduction of serum uric acid levels to achieve the target is particularly ambitious and/or the presence of comorbidities increases the risk of adverse effects. Associated comorbidities and cardiovascular risk factors should be also addressed as an important part of the management of chronic hyperuricemia and gout.

Topics: Allopurinol; Cardiovascular Diseases; Chronic Disease; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Kidney Diseases; Life Style; Patient Education as Topic; Thiazoles; Xanthine Oxidase

Gout is a common disorder with clinical signs and symptoms resulting from inflammatory responses to monosodium urate crystals deposited in tissues from extracellular fluids saturated for urate. Long-term management of gout focuses on nonpharmacologic and pharmacologic means to achieve and maintain serum urate levels in a subsaturating range. Despite a firm understanding of gout pathophysiology, means to achieve certain diagnosis, and a variety of effective therapies, treatment outcomes remain suboptimal. In this review, available nonpharmacologic and pharmacologic therapies for chronic gout are discussed and a framework is provided for successful achievement and maintenance of goal-range serum urate levels.

Topics: Allopurinol; Benzbromarone; Chronic Disease; Febuxostat; Feeding Behavior; Gout; Gout Suppressants; Humans; Hyperuricemia; Polyethylene Glycols; Risk Reduction Behavior; Thiazoles; Urate Oxidase; Uricosuric Agents

Numerous experimental and clinical studies suggest that uric acid might have pathobiologic implications in the development and progression of hypertension, kidney disease, and coronary heart disease, among others, resulting in renewed interest in uric acid as a potential pathogenic mediator in these clinical conditions. Despite encouraging animal studies showing beneficial roles of allopurinol, clinical studies and randomized controlled trials remain scarce, and, despite available clinical evidence supporting a therapeutic role for allopurinol, multiple issues remain before routine use of allopurinol can be recommended for use in patients with hyperuricemia and hypertension, kidney disease, or coronary heart disease. These include a need for more robust clinical trial data that evaluate efficacy on hard clinical outcomes, optimal dose, duration of treatment, and the potential for serious allergic reactions. In this article we review the current available evidence describing the effects of allopurinol in hypertension, kidney disease, and coronary heart disease, highlighting unresolved issues surrounding allopurinol use for uric acid lowering in individuals without gout.

Topics: Allopurinol; Antihypertensive Agents; Cardiotonic Agents; Chronic Disease; Coronary Disease; Gout Suppressants; Humans; Hypertension, Renal; Randomized Controlled Trials as Topic; Uric Acid

Dietary supplements are frequently used for the treatment of several medical conditions, both prescribed by physicians or self administered. However, evidence of benefit and safety of these supplements is usually limited or absent.. To assess the efficacy and safety of dietary supplementation for people with chronic gout.. We performed a search in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL on 6 June 2013. We applied no date or language restrictions. In addition, we performed a handsearch of the abstracts from the 2010 to 2013 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conferences, checked the references of all included studies and trial registries.. We considered all published randomised controlled trials (RCTs) or quasi-RCTs that compared dietary supplements with no supplements, placebo, another supplement or pharmacological agents for adults with chronic gout for inclusion. Dietary supplements included, but were not limited to, amino acids, antioxidants, essential minerals, polyunsaturated fatty acids, prebiotic agents, probiotic agents and vitamins. The main outcomes were reduction in frequency of gouty attacks and trial participant withdrawal due to adverse events. We also considered pain reduction, health-related quality of life, serum uric acid (sUA) normalisation, function (i.e. activity limitation), tophus regression and the rate of serious adverse events.. We used standard methodological procedures expected by The Cochrane Collaboration.. We identified two RCTs (160 participants) that fulfilled our inclusion criteria. As these two trials evaluated different diet supplements (enriched skim milk powder (SMP) and vitamin C) with different outcomes (gout flare prevention for enriched SMP and sUA reduction for vitamin C), we reported the results separately.One trial including 120 participants, at moderate risk of bias, compared SMP enriched with glycomacropeptides (GMP) with unenriched SMP and with lactose over three months. Participants were predominantly men aged in their 50's who had severe gout. The frequency of acute gout attacks, measured as the number of flares per month, decreased in all three groups over the study period.The effects of enriched SMP (SMP/GMP/G600) compared with the combined control groups (SMP and lactose powder) at three months in terms of mean number of gout flares per month were uncertain (mean ± standard deviation (SD) flares per month: 0.49 ± 1.52 in SMP/GMP/G60 group versus 0.70 ± 1.28 in control groups; mean difference (MD) -0.21, 95% confidence interval (CI) -0.76 to 0.34; low-quality evidence). The number of withdrawals due to adverse effects was similar in both groups although again the results were imprecise (7/40 in SMP/GMP/G600 group versus 11/80 in control groups; risk ratio (RR) 1.27, 95% CI 0.53 to 3.03; low-quality evidence). The findings for adverse events were also uncertain (2/40 in SMP/GMP/G600 group versus 3/80 in control groups; RR 1.33, 95% CI 0.23 to 7.66; low-quality evidence). Gastrointestinal events were the most commonly reported adverse effects. Pain from self reported gout flares (measured on a 10-point Likert scale) improved slightly more in the SMP/GMP/G600 group compared with controls (mean ± SD reduction -1.97 ± 2.28 points in SMP/GMP/G600 group versus -0.94 ± 2.25 in control groups; MD -1.03, 95% CI -1.96 to -0.10; low-quality evidence). This was an absolute reduction of 10% (95% CI 20% to 1% reduction), which may not be of clinical relevance. Results were imprecise for the outcome improvement in physical function (mean ± SD Health Assessment Questionnaire (HAQ)-II (scale 0 to 3, 0 = no disability): 0.08 ± 0.23 in SMP/GMP/G60 group versus 0.11 ± 0.31 in control groups; MD -0.03, 95% CI -0.14 to 0.08; low-quality evidence). Similarly, results for sUA reduction were imprecise (mean ± SD reduction: -0.025 ± 0.067 mmol/L in SMP/GMP/G60 group versus -0.010 ± 0.069 in control groups; MD -0.01, 95% CI -0.04 to 0.01; low-quality evidence). Th. While dietary supplements may be widely used for gout, this review has shown a paucity of high-quality evidence assessing dietary supplementation.

Topics: Adult; Allopurinol; Animals; Ascorbic Acid; Chronic Disease; Dietary Supplements; Gout; Humans; Lactose; Milk; Peptides; Powders; Randomized Controlled Trials as Topic

Allopurinol, a xanthine oxidase inhibitor, is considered one of the most effective urate-lowering drugs and is frequently used in the treatment of chronic gout.. To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE on 14 January 2014. We also handsearched the 2011 to 2012 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts, trial registers and regulatory agency drug safety databases.. All randomised controlled trials (RCTs) or quasi-randomised controlled clinical trials (CCTs) that compared allopurinol with a placebo or an active therapy in adults with chronic gout.. We extracted and analysed data using standard methods for Cochrane reviews. The major outcomes of interest were frequency of acute gout attacks, serum urate normalisation, pain, function, tophus regression, study participant withdrawal due to adverse events (AE) and serious adverse events (SAE). We assessed the quality of the body of evidence for these outcomes using the GRADE approach.. We included 11 trials (4531 participants) that compared allopurinol (various doses) with placebo (two trials); febuxostat (four trials); benzbromarone (two trials); colchicine (one trial); probenecid (one trial); continuous versus intermittent allopurinol (one trial) and different doses of allopurinol (one trial). Only one trial was at low risk of bias in all domains. We deemed allopurinol versus placebo the main comparison, and allopurinol versus febuxostat and versus benzbromarone as the most clinically relevant active comparisons and restricted reporting to these comparisons here.Moderate-quality evidence from one trial (57 participants) indicated allopurinol 300 mg daily probably does not reduce the rate of gout attacks (2/26 with allopurinol versus 3/25 with placebo; risk ratio (RR) 0.64, 95% confidence interval (CI) 0.12 to 3.52) but increases the proportion of participants achieving a target serum urate over 30 days (25/26 with allopurinol versus 0/25 with placebo, RR 49.11, 95% CI 3.15 to 765.58; number needed to treat for an additional beneficial outcome (NNTB) 1). In two studies (453 participants), there was no significant increase in withdrawals due to AE (6% with allopurinol versus 4% with placebo, RR 1.36, 95% CI 0.61 to 3.08) or SAE (2% with allopurinol versus 1% with placebo, RR 1.93, 95% CI 0.48 to 7.80). One trial reported no difference in pain reduction or tophus regression, but did not report outcome data or measures of variance sufficiently and we could not calculate the differences between groups. Neither trial reported function.Low-quality evidence from three trials (1136 participants) indicated there may be no difference in the incidence of acute gout attacks with allopurinol up to 300 mg daily versus febuxostat 80 mg daily over eight to 24 weeks (21% with allopurinol versus 23% with febuxostat, RR 0.89, 95% CI 0.71 to 1.1); however more participants may achieve target serum urate level (four trials; 2618 participants) with febuxostat 80 mg daily versus allopurinol 300 mg daily (38% with allopurinol versus 70% with febuxostat, RR 0.56, 95% CI 0.48 to 0.65, NNTB with febuxostat 4). Two trials reported no difference in tophus regression between allopurinol and febuxostat over a 28- to 52-week period; but as the trialists did not provide variance, we could not calculate the mean difference between groups. The trials did not report pain reduction or function. Moderate-quality evidence from pooled data from three trials (2555 participant. Our review found low- to moderate-quality evidence indicating similar effects on withdrawals due to AEs and SAEs and incidence of acute gout attacks when allopurinol (100 to 600 mg daily) was compared with placebo, benzbromarone (100 to 200 mg daily) or febuxostat (80 mg daily). There was moderate-quality evidence of little or no difference in the proportion of participants achieving target serum urate when allopurinol was compared with benzbromarone. However, allopurinol seemed more successful than placebo and may be less successful than febuxostat (80 mg daily) in achieving a target serum urate level (6 mg/dL or less; 0.36 mmol/L or less) based on moderate- to low-quality evidence. Single studies reported no difference in pain reduction when allopurinol (300 mg daily) was compared with placebo over 10 days, and no difference in tophus regression when allopurinol (200 to 300 mg daily) was compared with febuxostat (80 mg daily). None of the trials reported on function, health-related quality of life or participant global assessment of treatment success, where further research would be useful.

Topics: Allopurinol; Benzbromarone; Chronic Disease; Colchicine; Febuxostat; Gout; Gout Suppressants; Humans; Probenecid; Randomized Controlled Trials as Topic; Thiazoles; Uric Acid

Uricosuric agents have long been used in the treatment of gout but there is little evidence regarding their benefit and safety in this condition.. To assess the benefits and harms of uricosuric medications in the treatment of chronic gout.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2013), Ovid MEDLINE and Ovid EMBASE for studies to the 13 May 2013. We also searched the World Health Organization Clinical Trials Registry, ClinicalTrials.gov and the 2011 to 2012 American College of Rheumatology and European League against Rheumatism abstracts. WE considered black box warnings and searched drug safety databases to identify and describe rare adverse events.. We considered all randomised controlled trials (RCTs) or quasi-randomised controlled trials (controlled clinical trials (CCTs)) that compared uricosuric medications (benzbromarone, probenecid or sulphinpyrazone) alone or in combination with another therapy (placebo or other active uric acid-lowering medication, or non-pharmacological treatment) in adults with chronic gout for inclusion.. Two review authors independently selected the studies for inclusion, extracted data and performed a risk of bias assessment. Main outcomes were frequency of acute gout attacks, serum urate normalisation, study participant withdrawal due to adverse events, total adverse events, pain reduction, function and tophus regression.. The search identified four RCTs and one CCT that evaluated the benefit and safety of uricosurics for gout. One study (65 participants) compared benzbromarone with allopurinol for a duration of four months; one compared benzbromarone with allopurinol (36 participants) for a duration of nine to 24 months; one study (62 participants) compared benzbromarone with probenecid for two months and one study (74 participants) compared benzbromarone with probenecid. One study (37 participants) compared allopurinol with probenecid. No study was completely free from bias.Low-quality evidence from one study (55 participants) comparing benzbromarone with allopurinol indicated uncertain effects in terms of frequency of acute gout attacks (4% with benzbromarone versus 0% with allopurinol; risk ratio (RR) 3.58, 95% confidence interval (CI) 0.15 to 84.13), while moderate-quality evidence from two studies (101 participants; treated for four to nine months) indicated similar proportions of participants achieving serum urate normalisation (73.9% with benzbromarone versus 60% with allopurinol; pooled RR 1.27, 95% CI 0.90 to 1.79). Low-quality evidence indicated uncertain differences in withdrawals due to adverse events (7.1% with benzbromarone versus 6.1% with allopurinol; pooled RR 1.25, 95% CI 0.28 to 5.62), and total adverse events (20% with benzbromarone versus 6.7% with allopurinol; RR 3.00, 95% CI 0.64 to 14.16). The study did not measure pain reduction, function and tophus regression.When comparing benzbromarone with probenecid, there was moderate-quality evidence based on one study (62 participants) that participants taking benzbromarone were more likely to achieve serum urate normalisation after two months (81.5% with benzbromarone versus 57.1% with probenecid; RR 1.43, 95% CI 1.02 to 2.00). This indicated that when compared with probenecid, five participants needed to be treated with benzbromarone in order to have one additional person achieve serum urate normalisation (number needed to treat for an additional beneficial outcome (NNTB) 5). However, the second study reported no difference in the absolute decrease in serum urate between these groups after 12 weeks. Low-quality evidence from two studies (129 participants) indicated uncertain differences between treatments in the frequency of acute gout attacks (6.3% with benzbromarone versus 10.6% with probenecid; pooled RR 0.73, 95% CI 0.09 to 5.83); fewer withdrawals due to adverse events with benzbromarone (2% with ben. There was moderate-quality evidence that there is probably no important difference between benzbromarone and allopurinol at achieving serum urate normalisation, but that benzbromarone is probably more successful than probenecid at achieving serum urate normalisation in people with gout. There is some uncertainty around the effect estimates, based on low-quality evidence from only one or two trials, on the number of acute gout attacks, the number of withdrawals due to adverse events or the total number of participants experiencing adverse events when comparing benzbromarone with allopurinol. However, when compared with probenecid, benzbromarone resulted in fewer withdrawals due to adverse events and fewer participants experiencing adverse events. Low-quality evidence from one small study indicated uncertain effects in the incidence of acute gout attacks when comparing probenecid with allopurinol therapy. We downgraded the evidence because of a possible risk of performance and other biases and imprecision.

Topics: Adult; Aged; Allopurinol; Benzbromarone; Chronic Disease; Controlled Clinical Trials as Topic; Female; Gout; Humans; Male; Middle Aged; Probenecid; Randomized Controlled Trials as Topic; Uric Acid; Uricosuric Agents

The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.

Topics: Allopurinol; Animals; Antihypertensive Agents; Apolipoprotein L1; Apolipoproteins; Black People; Causality; Chronic Disease; Diabetic Angiopathies; Diabetic Nephropathies; Disease Management; Disease Models, Animal; Genetic Predisposition to Disease; Glomerulosclerosis, Focal Segmental; Goals; Humans; Hypertension; Hypertension, Renal; Hyperuricemia; Kidney Diseases; Lipoproteins, HDL; Multicenter Studies as Topic; Polymorphism, Genetic; Randomized Controlled Trials as Topic; Rats

This communication provides a brief report on the studies evaluating the use of allopurinol for delay of kidney disease progression and a discussion of the current limitations and future research needed. To date, only 5 studies have reported a delay in the progression of kidney disease with allopurinol use; a sixth study is currently underway. Allopurinol does seem to delay the progression of kidney disease as measured by using serum creatinine and glomerular filtration rates in hyperuricemic patients with chronic kidney disease. However, randomized, double-blind, placebo-controlled trials enrolling more patients and controlling for confounding variables are needed to confirm these findings.

Topics: Allopurinol; Chronic Disease; Creatinine; Disease Progression; Glomerular Filtration Rate; Gout Suppressants; Humans; Hyperuricemia; Renal Insufficiency, Chronic

Gout is the most common inflammatory arthritis in men over 40 years and has an increasing prevalence among postmenopausal women. Lowering serum uric acid levels remains one of the primary goals in the treatment of chronic gout. In clinical trials, febuxostat has been shown to be effective in lowering serum uric acid levels to < 6.0 mg/dL.. To evaluate the benefits and harms of febuxostat for chronic gout.. We searched The Cochrane Library, MEDLINE, EMBASE, and International Pharmaceutical Abstracts from inception to July 2011. The ClinicalTrials.gov website was searched for references to trials of febuxostat. Our search did not include any restrictions.. Two authors independently reviewed the search results and disagreements were resolved by discussion. We included any controlled clinical trial or open label trial (OLT) using febuxostat at any dose.. Data and risk of bias were independently extracted by two authors and summarised in a meta-analysis. Continuous data were expressed as mean difference and dichotomous data as risk ratio (RR).. Four randomised trials and two OLTs with 3978 patients were included. Risk of bias differed by outcome, ranging from low to high risk of bias. Included studies failed to report on five to six of the nine outcome measures recommended by OMERACT. Patients taking febuxostat 120 mg and 240 mg reported more frequent gout flares than in the placebo group at 4 to 28 weeks (RR 1.7; 95% CI 1.3 to 2.3, and RR 2.6; 95% CI 1.8 to 3.7 respectively). No statistically significant differences were observed at 40 mg and 80 mg. Compared to placebo, patients on febuxostat 40 mg were 40.1 times more likely to achieve serum uric acid levels < 6.0 mg/dL at 4 weeks (95% CI 2.5 to 639), with an absolute treatment benefit of 56% (95% CI 37% to 71%). For febuxostat 80 mg and 120 mg, patients were 68.9 and 80.7 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit compared to placebo (95% CI 13.8 to 343.9, 95% CI 16.0 to 405.5), respectively; with an absolute treatment benefit of 75% and 87% (95% CI 68 to 80% and 81 to 91%), respectively. Total discontinuation rates were significantly higher in the febuxostat 80 mg group compared to placebo (RR 1.4; 95% CI 1.0 to 2.0, absolute risk increase 11%; 95% CI 3 to 19%). No other differences were observed.When comparing allopurinol to febuxostat at 24 to 52 weeks, the number of gout flares was not significantly different between the two groups, except for febuxostat 240 mg (RR 2.3; 95% CI 1.7 to 3.0). Patients on febuxostat 40 mg showed no statistically significant differences in benefits or harms. Patients on febuxostat 80 mg and 120 mg were 1.8 and 2.2 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit (95% CI 1.6 to 2.2, 95% CI 1.9 to 2.5) with an absolute treatment benefit of 29% and 44% (95% CI 25% to 33%, 95% CI 38% to 50%), respectively, at 24 to 52 weeks. Total discontinuation rates were higher for febuxostat 80 mg and 120 mg compared to allopurinol (RR 1.5; 95% CI 1.2 to 1.8, absolute risk increase 11%; 95% CI 6% to 16%; and RR 2.6; 95% CI 2.0 to 3.3, absolute risk increase 20%; 95% CI 3% to 14%, respectively). Discontinuations due to adverse events were similar across groups. Total adverse events were lower for febuxostat 80 mg and 120 mg compared with allopurinol (RR 0.93; 95% CI 0.87 to 0.99, absolute risk increase 6%; 95% CI 0.7% to 11%; and RR 0.90; 95% CI 0.84 to 0.96, absolute risk increase 8%; 95% CI 3% to 13%, respectively). No other relevant differences wer. Although the incidence of gout flares requiring treatment may be increased in patients taking febuxostat compared to placebo or allopurinol during early treatment, no such increase in gout flares was observed in the long-term follow-up study when compared to allopurinol. Febuxostat at any dose was shown to be beneficial in achieving serum uric acid levels < 6.0 mg/dL and reducing serum uric acid levels in the period from baseline to final visit when compared to placebo and to allopurinol. However, the grade of evidence ranged from low to high, which indicates that further research is needed.

Topics: Allopurinol; Chronic Disease; Febuxostat; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Male; Randomized Controlled Trials as Topic; Thiazoles

The pharmacology, pharmacokinetics, clinical efficacy, and safety of febuxostat are reviewed.. Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase for the management of hyperuricemia in patients with gout. The ability of febuxostat to decrease serum uric acid production through selective inhibition of enzyme xanthine oxidase has been established in short-term Phase II and III clinical trials and long-term open-label studies. Clinical studies have revealed that febuxostat lowers serum uric acid levels more potently than allopurinol while having minimal effects on other enzymes associated with purine and pyrimide metabolism. The most frequent adverse events reported in clinical trials with febuxostat were liver function abnormalities, nausea, arthralgias, and rash. More cardiovascular thromboembolic events occurred in randomized trials in patients treated with febuxostat. Although a causal relationship has not been established, patients should be monitored for signs and symptoms of myocardial infarction and stroke. Febuxostat is available as 40- and 80-mg tablets. The recommended starting dosage is 40 mg orally once daily. If serum uric acid concentrations are not less than 6 mg/dL after two weeks, the dosage can be increased to 80 mg orally once daily. Dosage adjustments are not needed in elderly patients or patients with mild or moderate renal or hepatic impairment.. Febuxostat is efficacious as a second-line therapy in lowering serum uric acid levels in patients with gout. Febuxostat may be an alternative for patients with gout who are unable to take allopurinol due to hypersensitivity, intolerance, or lack of efficacy.

Topics: Allopurinol; Animals; Chronic Disease; Clinical Trials as Topic; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Thiazoles; Xanthine Oxidase

Complications and mortality of heart failure are high, despite the availability of several forms of treatment. Uric acid, the end product of purine metabolism would actively participate in the pathophysiology of heart failure. However, there is no consensus about its action in cardiovascular disease. Serum uric acid would have a protective antioxidant activity. This action could help to reduce or counteract the processes that cause or appear as a result of heart failure. However, these protective properties would vanish in the intracellular environment or in highly hydrophobic areas such as atherosclerotic plaques and adipose tissue. This review discusses the paradoxical action of uric acid in the pathophysiology of heart failure.

Topics: Animals; Biomarkers; Chronic Disease; Heart Failure; Humans; Oxidative Stress; Uric Acid; Xanthine Oxidase

Topics: Animals; Chronic Disease; Febuxostat; Heart Failure; Humans; Reactive Oxygen Species; Thiazoles; Xanthine Oxidase

Gout is a common disease and the prevalence is increasing. Chronic hyperuricemia (uric acid serum levels >6.8 mg/dL) is a key feature. Treating to a target uric acid level of 6.0 mg/dL is recommended. In addition to cochicine, probenecid, and allopurinol, feboxostat is a new option for urate-lowering therapy.

Topics: Allopurinol; Antimetabolites; Chronic Disease; Colchicine; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Probenecid; Thiazoles; Uric Acid; Uricosuric Agents

It is suggested that hyperuricemia has a pathogenetical role in the onset and progression of hypertension and renal disease in both clinical studies and animal experiments. The treatment of hyperuricemia by allopurinol was reported to cause improvement of hypertension and renal function, and the withdrawal of allopurinol treatment was also reported to bring worsening of hypertension and acceleration of the rate of loss of renal function in the patients with chronic kidney disease (CKD). However, the necessity of treatment against hyperuricemia in CKD has to be warranted by large scale clinical experiments in the future.

Topics: Allopurinol; Animals; Chronic Disease; Disease Progression; Humans; Hypertension; Hyperuricemia; Kidney Diseases; Metabolic Syndrome; Risk Factors

The majority of patients with gout are cared for by primary care physicians. Although both the physician and patient may easily recognize the acute arthritis of gout, errors in selecting the most appropriate medication and proper dose are common. The clinical stages of gout include asymptomatic hyperuricemia, intermittent gouty arthritis, and chronic tophaceous gout. Treatment of gout is usually considered after the first attack of arthritis, typically podagra. The aims of treatment are to alleviate the pain and inflammation associated with acute attacks, prevent future attacks, and decrease uric acid levels. Confusion frequently arises because certain medications such as colchicine may have dual purposes: to treat an acute attack and to suppress future attacks. The purpose of this management update is to provide practical advice about prescribing the proper medication considering both treatment goals and patient comorbidities.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Gouty; Chronic Disease; Colchicine; Drug Therapy, Combination; Family Practice; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Pain Measurement; Prognosis; Risk Assessment; Severity of Illness Index; Treatment Outcome; Uric Acid

Topics: Animals; Bacteria; Bacterial Physiological Phenomena; Bacterial Translocation; Chronic Disease; Cytokines; Diuretics; Fermentation; Humans; Inflammation; Intestinal Absorption; Intestines; Iron; Iron Chelating Agents; Kidney Diseases; Probiotics; Rats; Reactive Oxygen Species; Uremia; Xanthine Oxidase

The pathophysiologic understanding of chronic heart failure (CHF) has shifted from a mere hemodynamic disorder to a much more complex approach including changes and imbalances in neurohormonal, immune, and metabolic functions. Among metabolic abnormalities, hyperuricemia is a constant finding in CHF. The xanthine oxidase metabolic pathway increasingly is appreciated as an important contributor to both symptoms of CHF as well as progression of the disease. Recent data suggest hyperuricemia to be an independent marker of impaired prognosis in CHF. In this article, the significance of the xanthine oxidase metabolic pathway in CHF is discussed. Data on xanthine oxidase inhibition are reviewed, which suggest a beneficial effect of therapeutically targeting this enzymatic pathway.

Topics: Allopurinol; Animals; Biomarkers; Blood Flow Velocity; Blood Vessels; Chronic Disease; Disease Progression; Endothelium, Vascular; Enzyme Inhibitors; Heart Failure; Humans; Hyperuricemia; Prognosis; Uric Acid; Xanthine Oxidase

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiac Pacing, Artificial; Cardiography, Impedance; Cardiomyopathy, Dilated; Chronic Disease; Clinical Trials as Topic; Comorbidity; Disease Management; Enoximone; Heart Failure; Hemodynamics; Humans; Kidney Diseases; Natriuretic Peptide, Brain; Natriuretic Peptides; Nitric Oxide; Nitric Oxide Synthase; Pacemaker, Artificial; Phosphodiesterase Inhibitors; Practice Guidelines as Topic; Xanthine Oxidase

Chronic prostatitis is a condition that causes men substantial morbidity through the associated constellation of urinary symptoms, sexual dysfunction, and pelvic pain. The etiology of chronic prostatitis is unknown, and the many and varied treatments for chronic prostatitis reflect in part this knowledge gap. One novel etiologic theory is that the reflux of urine into prostatic ducts causes prostatic inflammation via high concentrations of purine and pyrimidine base-containing metabolites in prostatic secretions. This theory has led to the use of allopurinol for treatment of chronic prostatitis in hopes of lowering prostatic levels of uric acid and improving symptoms.. To determine the effects of allopurinol in the treatment of chronic prostatitis. Trials were searched in computerized general and specialized databases (MEDLINE, Cochrane Library, Cochrane Prostate Group database), bibliographies of obtained articles, and direct contact with authors.. All randomized trials of allopurinol versus placebo used to treat patients with chronic prostatitis. Acute prostatitis, bacterial prostatitis, and asymptomatic prostatitis were excluded. The main outcome measure was the change in patient-reported discomfort.. The reviewers extracted the data independently for the outcomes of change in patient-reported discomfort, investigator graded prostate pain, leukocyte counts, and biochemical indices.. In this update, no new trials were identified (08/2002). Only one trial with 54 men lasting 240 days (with 330 days of follow-up) met study inclusion criteria. There was a statistically significant change favoring allopurinol in patient-reported discomfort between the study and control groups at follow-up. Between days 45-225, the mean score was -0.95 (s.d. 0.19) for the allopurinol group (7 men), compared with -0.47 (s.d. 0.21) for the placebo group (7 men). The weighted mean difference (WMD) was -0.48 (95%CI -0.690, -0.270). The mean score between days 45-135 was -1.08 (s.d. 1.29) for the 25 men in the allopurinol group, compared with -0.21 (sd 0.97) for the 14 men in the control group. The WMD was -0.87 (95%CI -1.587, -0.153). The allopurinol group had significantly less investigator graded prostate pain and had lower levels of serum urate, urine urate, and expressed prostatic secretion urate and xanthine. No significant differences between the two groups regarding leukocyte counts were found. No patient receiving allopurinol had any significant side effects. Three patients in the placebo group dropped out because of side effects.. One small trial of allopurinol for treating chronic prostatitis showed improvements in patient-reported symptom improvement, investigator-graded prostate pain, and biochemical parameters. However, the data provided, the measures used, and the statistics presented do not make these findings convincing that changes in urine and prostatic secretion composition regarding purine and pyrimidine bases resulted in the relief of symptoms. Further studies of allopurinol treatment using standardized and validated outcomes measures and analyses are necessary to determine whether allopurinol is effective.

Topics: Allopurinol; Antimetabolites; Chronic Disease; Humans; Male; Prostatitis; Randomized Controlled Trials as Topic

To determine the effects of allopurinol in the treatment of chronic prostatitis. Trials were searched in computerized general and specialized databases (MEDLINE, Cochrane Library, Cochrane Prostate Group database), bibliographies of obtained articles, and direct contact with authors.. All randomized trials of allopurinol versus placebo used to treat patients with chronic prostatitis. Acute prostatitis, bacterial prostatitis, and asymptomatic prostatitis were excluded. The main outcome measure was the change in patient-reported discomfort.. The reviewers extracted the data independently for the outcomes of change in patient-reported discomfort, investigator graded prostate pain, leukocyte counts, and biochemical indices.. Only one trial with 54 men lasting 240 days (with 330 days of follow-up) met study inclusion criteria. There was a statistically significant change favoring allopurinol in patient-reported discomfort between the study and control groups at follow-up. Between days 45-225, the mean score was -0.95 (s.d. 0.19) for the allopurinol group (7 men), compared with -0.47 (s.d. 0.21) for the placebo group (7 men). The weighted mean difference (WMD) was -0.48 (95%CI -0.690, -0.270). The mean score between days 45-135 was -1.08 (s.d. 1.29) for the 25 men in the allopurinol group, compared with -0.21 (sd 0.97) for the 14 men in the control group. The WMD was -0.87 (95%CI -1.587, -0.153). The allopurinol group had significantly less investigator graded prostate pain and had lower levels of serum urate, urine urate, and expressed prostatic secretion urate and xanthine. No significant differences between the two groups regarding leukocyte counts were found. No patient receiving allopurinol had any significant side effects. Three patients in the placebo group dropped out because of side effects.. One small trial of allopurinol for treating chronic prostatitis showed improvements in patient-reported symptom improvement, investigator-graded prostate pain, and biochemical parameters. However, the data provided, the measures used, and the statistics presented do not make these findings convincing that changes in urine and prostatic secretion composition regarding purine and pyrimidine bases resulted in the relief of symptoms. Further studies of allopurinol treatment using standardized and validated outcomes measures and analyses are necessary to determine whether allopurinol is effective.

Topics: Allopurinol; Antimetabolites; Chronic Disease; Humans; Male; Prostatitis

For the management of acute gouty arthritis, non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice. In recent years, the use of colchicine has declined because of its frequent adverse reactions, and its reduced efficacy when administered more than 24 hours after onset of an acute attack. Intra-articular corticosteroid therapy (e.g. methylprednisolone acetate) is indicated for the treatment of acute mono or oligoarticular gouty arthritis in aged patients, and in those with co-morbid conditions contraindicating therapy with either NSAIDs or colchicine. Oral corticosteroids (e.g. prednisone), and both parenteral corticotrophin (ACTH) and corticosteroids (e.g. intramuscular triamcinolone acetonide) are valuable, relatively safe alternate treatment modalities in those with polyarticular attacks. For the treatment of hyperuricaemia and chronic gouty arthritis, allopurinol is the preferred urate-lowering drug. Its toxicity in elderly individuals, those with renal impairment, and in cyclosporine-treated transplant patients can be minimised by adjusting the initial dose according to the patient's creatinine clearance. In those experiencing cutaneous reactions to allopurinol, cautious desensitisation to the drug can be achieved using a schedule of gradually increasing doses. The therapeutic usefulness of uricosuric drugs is limited by the presence of renal impairment, occurrence of intolerable side-effects, or concomitant intake of salicylates. They are particularly indicated in patients allergic to allopurinol and in those with massive tophi requiring combined therapy with both allopurinol and a uricosuric.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Arthritis, Gouty; Chronic Disease; Clinical Trials as Topic; Female; Gout; Gout Suppressants; Humans; Injections, Intra-Articular; Male; Middle Aged; Singapore; Treatment Outcome

Topics: Acute Disease; Adenosine; Allopurinol; Animals; Chronic Disease; Glutathione; Graft Rejection; Humans; Insulin; Intestine, Small; Organ Preservation; Organ Preservation Solutions; Raffinose; Reperfusion Injury; Transplantation, Homologous

Gout is a syndrome caused by an inflammatory response to the formation of monosodium urate monohydrate crystals which develop secondary to hyperuricaemia. Acute and chronic forms occur. Hyperuricaemia may be due to environmental and/or genetic factors. It most commonly affects middle-aged males. This article discusses the management of both acute and chronic gout.

Topics: Acute Disease; Adult; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Female; Gout; Humans; Male; Uricosuric Agents; Xanthine Oxidase

Topics: Animals; Chronic Disease; Collateral Circulation; Coronary Disease; False Positive Reactions; Free Radicals; Half-Life; Myocardial Infarction; Myocardial Reperfusion; Oxygen; Superoxide Dismutase; Tetrazolium Salts; Xanthine Oxidase

Gout is a clinical syndrome encompassing a group of metabolic diseases that are all characterized by abnormal uric acid metabolism. In its fullest form, gout is defined by: an increase in the serum urate concentration; characteristic, recurrent, acute arthritic attacks, with monosodium urate monohydrate crystals demonstrable in synovial fluid leukocytes; tophi, usually in and around joints of the extremities, composed of monosodium urate monohydrate deposits; renal disease, often accompanied by hypertension with glomerular, tubular, interstitial, and vascular involvement; and uric acid nephrolithiasis. Any combination of these manifestations may occur, although tophi and urate nephropathy rarely antedate gouty arthritis.

Topics: Acute Disease; Adult; Allopurinol; Anti-Inflammatory Agents; Arthritis; Arthrography; Calcinosis; Chronic Disease; Colchicine; Female; Gout; Humans; Kidney Calculi; Kidney Diseases; Middle Aged; Probenecid; Uric Acid

Topics: Allopurinol; Chemical and Drug Induced Liver Injury; Cholestasis; Chronic Disease; Female; Granuloma; Hepatitis; Humans; Indoles; Liver Cirrhosis; Methyldopa; Nitrofurantoin; Oxyphenisatin Acetate; Phenylbutazone

Topics: Allopurinol; Arthritis; Chronic Disease; Colchicine; Gout; Humans; Indomethacin; Naproxen; Phenylbutazone; Probenecid; Sulfinpyrazone; Uric Acid; Uricosuric Agents

Topics: Acute Disease; Adrenal Cortex Hormones; Allopurinol; Anemia; Autoimmune Diseases; Blood Coagulation Disorders; Blood Platelets; Blood Transfusion; Chronic Disease; Granulocytes; Humans; Infection Control; Leukemia; Uric Acid

Topics: Acute Disease; Allopurinol; Chronic Disease; Colchicine; Gout; Humans; Hydrogen-Ion Concentration; Kidney Calculi; Kidney Tubules; Probenecid; Purines; Sulfinpyrazone; Uric Acid; Uricosuric Agents

Topics: Acute Disease; Adrenal Cortex Hormones; Arthritis; Chronic Disease; Colchicine; Glomerular Filtration Rate; Gout; Phenylbutazone; Purines; Urate Oxidase; Uric Acid; Uricosuric Agents; Xanthine Oxidase

Hyperuricemia 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.. The 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.. The Excited-UA study would provide novel evidence for the clinical relevancy of xanthine oxidoreductase inhibitor treatment in patients with chronic heart failure and hyperuricemia.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Chronic Disease; Echocardiography; Enzyme Inhibitors; Heart Failure; Humans; Hyperuricemia; Middle Aged; Natriuretic Peptide, Brain; Nitriles; Peptide Fragments; Pyridines; Randomized Controlled Trials as Topic; Research Design; Xanthine Oxidase; Young Adult

We prospectively evaluated whether an effective 12-month uric acid-lowering therapy (ULT) with the available xanthine oxidase (XO) inhibitors allopurinol and febuxostat in patients with chronic tophaceous gout has an impact on oxidative stress and/or vascular function. Patients with chronic tophaceous gout who did not receive active ULT were included. After clinical evaluation, serum uric acid levels (SUA) and markers of oxidative stress were measured, and carotid-femoral pulse wave velocity (cfPWV) was assessed. Patients were then treated with allopurinol (n = 9) or with febuxostat (n = 8) to target a SUA level ≤ 360 μmol/L. After 1 year treatment, the SUA levels, markers of oxidative stress and the cfPWV were measured again. Baseline characteristics of both groups showed no significant differences except a higher prevalence of moderate impairment of renal function (estimated glomerular filtration rate <60 ml/min) in the febuxostat group. Uric acid lowering with either inhibitors of XO resulted in almost equally effective reduction in SUA levels. The both treatment groups did not differ in their baseline cfPWV (allopurinol group: 14.1 ± 3.4 m/s, febuxostat group: 13.7 ± 2.7 m/s, p = 0.80). However, after 1 year of therapy, we observed a significant cfPWV increase in the allopurinol group (16.8 ± 4.3 m/s, p = 0.001 as compared to baseline), but not in the febuxostat patients (13.3 ± 2.3 m/s, p = 0.55). Both febuxostat and allopurinol effectively lower SUA levels in patients with severe gout. However, we observed that febuxostat also appeared to be beneficial in preventing further arterial stiffening. Since cardiovascular events are an important issue in treating patients with gout, this unexpected finding may have important implications and should be further investigated in randomized controlled trials.

Topics: Aged; Allopurinol; Biomarkers; Chronic Disease; Enzyme Inhibitors; Febuxostat; Germany; Glomerular Filtration Rate; Gout; Gout Suppressants; Humans; Inflammation Mediators; Kidney; Male; Middle Aged; Oxidative Stress; Prospective Studies; Pulse Wave Analysis; Severity of Illness Index; Thiazoles; Time Factors; Treatment Outcome; Uric Acid; Vascular Stiffness; Xanthine Oxidase

NFAT5 (nuclear factor of activated T cells), a well-known osmoprotective factor, can be activated by isotonic stimuli such as Toll-like receptor (TLR) triggering. However, it is unclear how NFAT5 discriminates between isotonic and hypertonic stimuli to produce different functional and molecular outcomes. Here, we identified a novel XO-ROS-p38 MAPK-NFAT5 pathway (XO is xanthine oxidase, ROS is reactive oxygen species) that is activated in RAW 264.7 macrophages upon isotonic TLR stimulation. Unlike what is seen under hypertonic conditions, XO-derived ROS were selectively required for the TLR-induced NFAT5 activation and NFAT5 binding to the IL-6 promoter in RAW 264.7 macrophages under isotonic conditions. In mouse peritoneal macrophages and human macrophages, TLR ligation also induced NFAT5 activation, which was dependent on XO and p38 kinase. The involvement of XO in NFAT5 activation by TLR was confirmed in RAW 264.7 macrophages implanted in BALB/c mice. Moreover, allopurinol, an XO inhibitor, suppressed arthritis severity and decreased the expression of NFAT5 and IL-6 in splenic macrophages in C57BL/6 mice. Collectively, these data support a novel function of the XO-NFAT5 axis in macrophage activation and TLR-induced arthritis, and suggest that XO inhibitor(s) could serve as a therapeutic agent for chronic inflammatory arthritis.

Topics: Animals; Arthritis; Cell Line; Chronic Disease; Female; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred BALB C; Reactive Oxygen Species; Toll-Like Receptors; Transcription Factors; Xanthine Oxidase

Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy.. Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR.. Among 212 patients randomized in the RCTs, 155 (73%) had ≥ 1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo).. Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy.. NCT00325195, NCT01356498.

Topics: Adult; Aged; Allopurinol; Chronic Disease; Double-Blind Method; Drug Administration Schedule; Drug Resistance; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Polyethylene Glycols; Time Factors; Treatment Outcome; Urate Oxidase; Uric Acid

Even though the use of combined drugs has been proved to be effective in other chronic infections, assessment of combined treatment of antiparasitic drugs in human Chagas' disease has not been performed. Herein, a pilot study was conducted to evaluate the tolerance and side effects of a sequential combined treatment of two antiparasitic drugs, allopurinol and benznidazole, in the chronic phase of Trypanosoma cruzi infection.. Changes in total and T. cruzi-specific T and B cells were monitored during a median follow-up of 36 months. Allopurinol was administered for 3 months (600 mg/day) followed by 30 days of benznidazole (5 mg/kg/day) in 11 T. cruzi-infected subjects.. The combined sequential treatment of allopurinol and benznidazole was well tolerated. The levels of T. cruzi-specific antibodies significantly decreased after sequential combined treatment, as determined by conventional serology and by a multiplex assay using recombinant proteins. The frequency of T. cruzi-specific interferon-γ-producing T cells significantly increased after allopurinol treatment and decreased to background levels following benznidazole administration in a substantial proportion of subjects evaluated. The levels of total naive (CD45RA + CCR7 + CD62L+) CD4 + and CD8 + T cells were restored after allopurinol administration and maintained after completion of the combined drug protocol, along with a decrease in T cell activation in total peripheral CD4 + and CD8 + T cells.. This pilot study shows that the combination of allopurinol and benznidazole induces significant modifications in T and B cell responses indicative of a reduction in parasite burden, and sustains the feasibility of administration of two antiparasitic drugs in the chronic phase of Chagas' disease.

Topics: Adult; Allopurinol; Antiprotozoal Agents; B-Lymphocytes; Chagas Disease; Chronic Disease; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitroimidazoles; Pilot Projects; T-Lymphocytes; Treatment Outcome; Trypanosoma cruzi

Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)-conjugated mammalian recombinant uricase, was developed to fulfill this need.. To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout.. Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406.. Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group).. Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6.. In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008).. Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo.. clinicaltrials.gov Identifier: NCT00325195.

Topics: Allopurinol; Chronic Disease; Double-Blind Method; Drug Administration Schedule; Drug Resistance; Enzymes, Immobilized; Female; Gout; Gout Suppressants; Humans; Infusions, Intravenous; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome; Urate Oxidase; Uric Acid

Patients with chronic heart failure (HF) are characterized by alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) levels. However, the impact of hypolipidemic and antioxidant treatment in MMPs and TIMPs is unknown. In the present study, we sought to compare the effects of statins and xanthine oxidase inhibitors on circulating levels of MMPs and TIMPs in patients with chronic HF.. Forty-two clinically stable patients with mild to moderate HF were randomized to receive rosuvastatin 10 mg or allopurinol 300 mg daily and followed up for 1 month. Serum levels of MMP-2, -9, TIMP-1, and -2 were measured before and after treatment.. Levels of MMP-2 and -9 were significantly decreased in the rosuvastatin group (from 251±52 ng/ml and 400±206 ng/ml to 215±47 ng/ml and 309±166 ng/ml, p<0.001 and p<0.05 respectively), but not in the allopurinol group. In the rosuvastatin group, TIMP-2 levels were significantly increased (from 85±17 ng/ml to 93±16 ng/ml, p<0.05), while TIMP-1 remained unchanged. In the allopurinol group, no significant changes were observed regarding the levels of TIMPs.. Short-term rosuvastatin but not allopurinol administration decreases MMP-2 and -9 and increases TIMP-2 levels.

Topics: Aged; Allopurinol; Biomarkers; Chronic Disease; Drug Therapy, Combination; Extracellular Matrix; Female; Fluorobenzenes; Free Radical Scavengers; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2

Studies indicate that myeloperoxidase (MPO) is associated with disease progression and severity in heart failure (HF), while it may provide a mechanistic link between inflammation and adverse cardiac remodeling. The mechanisms that regulate MPO are unclear, while it is unknown whether specific treatments such as HMG-CoA reductase inhibitors and xanthine oxidase inhibitors may modify MPO. Therefore in the present study we examined the effects of rosuvastatin and allopurinol on MPO levels in patients HF.. Sixty clinically stable patients with systolic HF were randomized to receive rosuvastatin 10mg/day, allopurinol 300mg/day or placebo and followed up for 1 month. Plasma levels of MPO and serum levels of soluble CD40 ligand, interleukin-6, and oxidized LDL were determined using ELISA. All measurements were made before and after 1-month treatment.. Rosuvastatin significantly reduced plasma levels of MPO (p=0.003), which remained unchanged in the other groups. Furthermore, the change of MPO levels in the rosuvastatin-treated group was significantly different compared with the other groups (p<0.05). Rosuvastatin administration also led to a significant decrease in oxidized LDL (p=0.009), while the other inflammatory markers remained unchanged in all groups. In the total population, a significant correlation was observed between the baseline levels of MPO and hsCRP (r=0.275, p=0.027), fibrinogen (r=0.278, p=0.025), and sCD40L (r=0.288, p=0.021).. Short-term treatment with rosuvastatin regulates inflammatory process in patients with heart failure by significantly reducing plasma levels of MPO. This finding reveals a novel pleiotropic effect of statins in patients with heart failure, and provides further insights into the pathophysiological mechanisms of MPO in heart failure.

Topics: Aged; Allopurinol; Biomarkers; Cholesterol; Cholesterol, LDL; Chronic Disease; Female; Fluorobenzenes; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Peroxidase; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Triglycerides

Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease.. We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes.. Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 +/- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy.. Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.

Topics: Aged; Allopurinol; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Chi-Square Distribution; Chronic Disease; Disease Progression; Glomerular Filtration Rate; Gout Suppressants; Hospitalization; Humans; Hyperuricemia; Inflammation Mediators; Kaplan-Meier Estimate; Kidney Diseases; Middle Aged; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Spain; Time Factors; Treatment Outcome; Uric Acid

Experimental evidence suggests that xanthine oxidase inhibitors can reduce myocardial oxygen consumption for a particular stroke volume. If such an effect also occurs in man, this class of inhibitors could become a new treatment for ischaemia in patients with angina pectoris. We ascertained whether high-dose allopurinol prolongs exercise capability in patients with chronic stable angina.. 65 patients (aged 18-85 years) with angiographically documented coronary artery disease, a positive exercise tolerance test, and stable chronic angina pectoris (for at least 2 months) were recruited into a double-blind, randomised, placebo-controlled, crossover study in a hospital and two infirmaries in the UK. We used computer-generated randomisation to assign patients to allopurinol (600 mg per day) or placebo for 6 weeks before crossover. Our primary endpoint was the time to ST depression, and the secondary endpoints were total exercise time and time to chest pain. We did a completed case analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 82040078.. In the first treatment period, 31 patients were allocated to allopurinol and 28 were analysed, and 34 were allocated to placebo and 32 were analysed. In the second period, all 60 patients were analysed. Allopurinol increased the median time to ST depression to 298 s (IQR 211-408) from a baseline of 232 s (182-380), and placebo increased it to 249 s (200-375; p=0.0002). The point estimate (absolute difference between allopurinol and placebo) was 43 s (95% CI 31-58). Allopurinol increased median total exercise time to 393 s (IQR 280-519) from a baseline of 301 s (251-447), and placebo increased it to 307 s (232-430; p=0.0003); the point estimate was 58 s (95% CI 45-77). Allopurinol increased the time to chest pain from a baseline of 234 s (IQR 189-382) to 304 s (222-421), and placebo increased it to 272 s (200-380; p=0.001); the point estimate was 38 s (95% CI 17-55). No adverse effects of treatment were reported.. Allopurinol seems to be a useful, inexpensive, well tolerated, and safe anti-ischaemic drug for patients with angina.. British Heart Foundation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Angina Pectoris; Blood Pressure; C-Reactive Protein; Cardiovascular Agents; Chronic Disease; Cross-Over Studies; Double-Blind Method; Electrocardiography; Enzyme Inhibitors; Exercise Tolerance; Female; Follow-Up Studies; Heart Rate; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Nitroglycerin; Placebos; Time Factors; Vasodilator Agents; Xanthine Oxidase; Young Adult

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide-dependent vasodilation. In 113 patients with chronic heart failure (CHF) and 26 controls, ADMA level was studied in relation to peripheral blood flow and vasodilator capacity. Further, the effects of allopurinol on concentrations of reactive oxygen species (ROS) and ADMA and peripheral vasodilator capacity were tested in a double-blind design. ADMA level was found to be elevated in CHF patients as compared with controls and increased in parallel with New York Heart Association (NYHA) class and exercise capacity (all P < 0.0001). The level of ADMA predicted resting blood flow (P < 0.05) and postischemic vasodilator capacity (P < 0.001). Sixty eight patients died during the follow-up period. The level of ADMA predicted survival after multivariable adjustment (P = 0.04). Allopurinol reduced uric acid (UA) concentration (P < 0.001) and decreased ROS concentration (allantoin, P < 0.01). Allopurinol lowered ADMA concentration (P = 0.02); postischemic vasodilation as well as endothelium-dependent vasodilation (both P < 0.05) improved. ADMA may be a pathophysiologic factor that is modulated by ROS accumulation and contributes to impaired vascular regulation in CHF.

Topics: Aged; Allopurinol; Arginine; Chronic Disease; Citrulline; Cross-Sectional Studies; Double-Blind Method; Female; Free Radical Scavengers; Heart Failure; Humans; Male; Middle Aged; Reactive Oxygen Species; Uric Acid; Vasodilation

Thirty-five individuals from endemic areas of Central Brazil (age range, 18-64 years; 19 women) in the chronic phase of Chagas disease, with positive serology and presence of circulating parasites detected by one or more recent positive xenodiagnosis, were selected for this study. Allopurinol (900 mg/d) or placebo was administered in a double-blind clinical trial for 60 days. After codes were broken, 23 had been allocated to the intervention group and 12 to the placebo group. Side effects were observed in 11 patients in the intervention group and in 1 in the placebo group. Seventeen patients in the intervention group and 10 in the placebo group completed the trial. Follow-up was performed by monthly xenodiagnosis and serologic tests every 3 months during the first year and at the end of the trial. Xenodiagnosis remained positive in all 17 of the treated group and in all 10 of the placebo group. Serologic tests were persistently positive in both groups after treatment. We concluded that, at the doses used, allopurinol was not effective to clear, in our region, Trypanosoma cruzi from peripheral blood of infected individuals.

Topics: Adolescent; Adult; Allopurinol; Animals; Antiparasitic Agents; Chagas Disease; Chronic Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Treatment Failure; Trypanosoma cruzi

To study whether the effect of allopurinol on improvement of endothelial dysfunction in chronic heart failure (CHF) translates into improved exercise capacity and to examine whether allopurinol also improves B-type natriuretic peptide (BNP), the other important prognostic marker of CHF.. Randomised, double blind, placebo controlled crossover trial.. Teaching hospital.. 50 patients with CHF (New York Heart Association functional classes II and III) were recruited.. 50 patients with CHF were randomly assigned to three months' treatment with allopurinol (300 mg/day) or placebo. At two and three months into treatment, they underwent a modified Bruce exercise protocol and a six minute walk test. Blood was taken for BNP and haemoglobin analysis.. Neither exercise test was altered by allopurinol. However, plasma BNP concentrations fell significantly (p = 0.035) with allopurinol (11.9 pmol/l) versus placebo (14.4 pmol/l). Haemoglobin concentrations also fell highly significantly with allopurinol (p = 0.001).. An important negative finding is that despite high hopes for it, allopurinol had no effect on exercise capacity in CHF. On the other hand, allopurinol did reduce BNP, which is the best available surrogate marker for prognosis in CHF.

Topics: Aged; Allopurinol; Analysis of Variance; Biomarkers; Chronic Disease; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; Exercise Tolerance; Female; Heart Failure; Hemoglobins; Humans; Male; Natriuretic Peptide, Brain; Ventricular Dysfunction, Left; Xanthine Oxidase

To assess the short-term urate-lowering effect of fenofibrate in men on long-term allopurinol therapy for hyperuricaemia and gout.. Ten male patients (38-74 yr) with a history of chronic tophaceous or recurrent acute gout with hyperuricaemia and on established allopurinol at 300-900 mg/day for > or =3 months were studied in an open-crossover study of fenofibrate therapy. Allopurinol at the established dose was continued throughout the study. Clinical and biochemical assessments (serum urate and creatinine, 24-h urinary excretion of urate and creatinine, liver function tests, creatine kinase and fasting serum lipids) were undertaken at: (i) baseline, (ii) after 3 weeks of once-daily therapy with micronized fenofibrate (Lipantil Micro) at 200 mg and (iii) 3 weeks after fenofibrate was withdrawn.. Fenofibrate was associated with a 19% reduction in serum urate after 3 weeks of treatment (mean+/-S.E. 0.37+/-0.04 vs 0.30+/-0.02 mM/l; P=0.004). The effect was reversed after a 3-week fenofibrate withdrawal period (0.30+/-0.02 vs 0.38+/-0.03 mM/l). There was a rise in uric acid clearance with fenofibrate treatment of 36% (7.2+/-0.9 vs 11.4+/-1.6 ml/min, normal range 6-11; P=0.006) without a significant change in creatinine clearance. Both total cholesterol and serum triglycerides were also reduced. No patient developed acute gout whilst taking fenofibrate.. Fenofibrate has a rapid and reversible urate-lowering effect in patients with hyperuricaemia and gout on established allopurinol prophylaxis. Fenofibrate may be a potential new treatment for hyperuricaemia and the prevention of gout, particularly in patients with coexisting hyperlipidaemia or those resistant to conventional therapy for hyperuricaemia.

Topics: Acute Disease; Adult; Aged; Alkaline Phosphatase; Allopurinol; Arthritis, Gouty; Chronic Disease; Cross-Over Studies; Drug Therapy, Combination; Fenofibrate; Gout; Gout Suppressants; Humans; Hyperuricemia; Hypolipidemic Agents; Lipids; Male; Middle Aged; Recurrence; Uric Acid

Impaired flow-dependent, endothelium-mediated vasodilation (FDD) in patients with chronic heart failure (CHF) results, at least in part, from accelerated degradation of nitric oxide by oxygen radicals. The mechanisms leading to increased vascular radical formation, however, remain unclear. Therefore, we determined endothelium-bound activities of extracellular superoxide dismutase (ecSOD), a major vascular antioxidant enzyme, and xanthine-oxidase, a potent radical producing enzyme, and their relation to FDD in patients with CHF.. ecSOD and xanthine-oxidase activities, released from endothelium into plasma by heparin bolus injection, were determined in 14 patients with CHF and 10 control subjects. FDD of the radial artery was measured using high-resolution ultrasound and was assessed before and after administration of the antioxidant vitamin C (25 mg/min; IA). In patients with CHF, endothelium-bound ecSOD activity was substantially reduced (5.0+/-0.7 versus 14.4+/-2.6 U x mL(-1) x min(-1); P<0.01) and closely related to FDD (r=0.61). Endothelium-bound xanthine-oxidase activity was increased by >200% (38+/-10 versus 12+/-4 nmol O2*- x microL(-1); P<0.05) and inversely related to FDD (r=-0.35) in patients with CHF. In patients with low ecSOD and high xanthine-oxidase activity, a greater benefit of vitamin C on FDD was observed, ie, the portion of FDD inhibited by radicals correlated negatively with ecSOD (r=-0.71) but positively with xanthine-oxidase (r=0.75).. These results demonstrate that both increased xanthine-oxidase and reduced ecSOD activity are closely associated with increased vascular oxidative stress in patients with CHF. This loss of vascular oxidative balance likely represents a novel mechanism contributing to endothelial dysfunction in CHF.

Topics: Antioxidants; Ascorbic Acid; Chronic Disease; Endothelium, Vascular; Enzyme Activation; Extracellular Space; Female; Free Radicals; Heart Failure; Humans; Male; Middle Aged; Oxidative Stress; Radial Artery; Regional Blood Flow; Superoxide Dismutase; Ultrasonography; Vasodilation; Xanthine Oxidase

In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)-derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies.. In 10 CHF patients with normal serum uric acid (UA) levels (315+/-42 micromol/L) and 9 patients with elevated UA (535+/-54 micromol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 microg/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (P<0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558+/-21 micromol/L, range 455 to 743 micromol/L), treatment reduced UA by >120 micromol/L in all patients (mean reduction 217+/-15 micromol/L, P<0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (+24%, P=0.027) and legs (+23%, P=0.029). Flow-dependent flow improved by 58% in arms (P=0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (P<0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (r=0.63, P<0.05).. In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.

Topics: Administration, Oral; Aged; Allantoin; Allopurinol; Blood Flow Velocity; Chronic Disease; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; Forearm; Heart Failure; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Oxidative Stress; Regional Blood Flow; Uric Acid; Vasodilation; Xanthine Oxidase

Increased oxidative stress in chronic heart failure is thought to contribute to endothelial dysfunction. Xanthine oxidase produces oxidative stress and therefore we examined whether allopurinol improved endothelial dysfunction in chronic heart failure.. We performed a randomized, placebo-controlled, double-blind crossover study on 11 patients with New York Heart Association class II-III chronic heart failure, comparing 300 mg allopurinol daily (1 month) versus placebo. Endothelial function was assessed by standard forearm venous occlusion plethysmography with acetylcholine, nitroprusside, and verapamil. Plasma malondialdehyde levels were also compared to assess significant changes in oxidative stress. Allopurinol significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean+/-SEM]: 181+/-19% versus 120+/-22% allopurinol versus placebo; P=0.003). There were no significant differences in the forearm blood flow changes between the placebo and allopurinol treatment arms with regard to sodium nitroprusside or verapamil. Plasma malondialdehyde was significantly reduced with allopurinol treatment (346+/-128 nmol/L versus 461+/-101 nmol/L, allopurinol versus placebo; P=0.03), consistent with reduced oxidative stress with allopurinol therapy.. We have shown that allopurinol improves endothelial dysfunction in chronic heart failure. This raises the distinct possibility that allopurinol might reduce cardiovascular events and even improve exercise capacity in chronic heart failure.

Topics: Aged; Allopurinol; Antioxidants; Blood Pressure; Chronic Disease; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; Female; Forearm; Heart Failure; Heart Rate; Humans; Male; Malondialdehyde; Regional Blood Flow; Vasodilator Agents; Xanthine Oxidase

To determine if lowering of serum uric acid (SUA) concentrations below 6 mg/dl or longer duration of lowered SUA will result in depletion of urate crystals from the knee joints and prevent further attacks of gout.. A prospective study was initiated 10 years ago at Philadelphia VA Medical Center to attempt to maintain SUA levels of patients with crystal proven gout at < 6.0 mg/dl. We recalled all 57 patients who were available during 1999. Patients were divided into 2 groups: Group A, with SUA still > 6 mg/dl, and Group B, with SUA < or = 6 mg/dl. A knee joint aspirate was requested from all asymptomatic Group B patients and many in Group A. Aspirates were examined by polarized light microscopy for identification of crystals.. There were no differences between the groups in age, sex, duration of gout, or serum creatinine. Group A (n = 38) had a mean of 6 attacks of gout for the recent year, those with tophi having the most frequent attacks. Among the 16 patients in this group who agreed to knee aspiration, monosodium urate (MSU) crystals were found in 14, although they were asymptomatic at the time. Nineteen patients (Group B) were able to maintain serum urate levels < or = 6 mg/dl for > 12 months. Nearly half of them had no attack of gout for 2 or more years, with a mean of 1 attack in the last year for the whole group. Three patients in whom tophi were found did not have major flares of gout within the past year. Knee joint aspiration was done on 16 asymptomatic patients. Seven (44%) still had MSU crystals present in their knees. Patients in this group who were taking prophylactic colchicine did not differ with respect to the character of synovial fluid from those who had discontinued it for up to several years, although the frequency of attacks was less in those who continued colchicine.. A majority of patients were able to deplete urate crystal stores in their knee joint fluids when their SUA levels were kept to < or = 6 mg/dl for several years. The mechanisms for persistence in some patients, and whether such crystals have clinical implications, are not known. Patients with chronic gout need serum urate concentrations to be kept low to prevent further attacks.

Topics: Allopurinol; Chronic Disease; Colchicine; Crystallization; Extracellular Space; Follow-Up Studies; Gout; Gout Suppressants; Humans; Knee Joint; Male; Prospective Studies; Treatment Outcome; Uric Acid

Four hundred four patients with chronic Chagas' disease were treated with itraconazole (6 mg/kg of body weight/day for 120 days), allopurinol (8.5 mg/kg of body weight/day for 60 days), or with a placebo of pure starch. Patients were monitored over a period of four years by clinical examination, serology, xenodiagnosis, hemoculture, and electrocardiogram. Drug tolerance was good, with only four treatments discontinued due to side effects that subsided after suspension of treatment. Parasitologic cure was evident in 44% of the those treated with allopurinol and 53% of those treated with itraconazole, and the electrocardiographic evaluation showed normalization in 36.5% and 48.2%, respectively, of patients with chronic or recent cardiopathy.

Topics: Adolescent; Adult; Allopurinol; Animals; Antibodies, Protozoan; Antifungal Agents; Antimetabolites; Biological Assay; Chagas Cardiomyopathy; Chagas Disease; Child; Chronic Disease; Double-Blind Method; Electrocardiography; Follow-Up Studies; Humans; Insect Vectors; Itraconazole; Middle Aged; Nymph; Triatoma; Trypanosoma cruzi

To study the efficacy of allopurinol and benzbromarone to reduce serum urate concentrations in patients with primary chronic gout.. Prospective, parallel, open study of 86 consecutive male patients with primary chronic gout. Forty nine patients (26 normal excretors and 23 under excretors) were given allopurinol 300 mg/day and 37 under excretors benzbromarone 100 mg/day. After achieving steady plasma urate concentrations with such doses, treatment was then adjusted to obtain optimal plasmatic urate concentrations (under 6 mg/dl).. Patients receiving allopurinol 300 mg/day showed a mean reduction of plasmatic urate of 2.75 mg/dl (from 8.60 to 5.85 mg/dl) and 3.34 mg/dl (from 9.10 to 5.76 mg/dl) in normal excretors and under excretors respectively. Patients receiving benzbromarone 100 mg/day achieved a reduction of plasmatic urate of 5.04 mg/dl (from 8.58 to 3.54 mg/dl). Fifty three per cent of patients receiving allopurinol and 100% receiving benzbromarone achieved optimal plasma urate concentrations at such doses. The patients with poor results with allopurinol 300 mg/day achieved a proper plasma urate concentration with allopurinol 450 to 600 mg/day, the mean final dose being 372 mg/day. Renal function improved and no case of renal lithiasis was observed among benzbromarone treated patients, whose mean final dose was 76 mg/day.. Benzbromarone is very effective to control plasma urate concentrations at doses ranging from 50 to 100 mg/day. Uricosuric treatment is a suitable approach to the treatment of patients with gout who show underexcretion of urate.

Topics: Adult; Aged; Allopurinol; Benzbromarone; Chronic Disease; Drug Administration Schedule; Gout; Gout Suppressants; Humans; Male; Middle Aged; Prospective Studies; Uric Acid; Uricosuric Agents

A dosage of 300 mg/d of allopurinol was not effective in reducing pain or improving activities of daily living in chronic pancreatitis.. Allopurinol prevents the generation of oxygen-derived free radicals by inhibiting xanthine oxidase. The purpose of this study was to determine whether allopurinol is effective in reducing pain of chronic pancreatitis.. Thirteen patients with chronic pancreatitis who were experiencing abdominal pain requiring medication at least three times each week entered a randomized, double-blind, two-period crossover clinical trial. Patients evaluated their pain daily using a categorical pain intensity scale, numeric pain intensity scale, and a visual analog scale, and weekly completed a McGill Pain Questionnaire and activities of daily living (ADL) questionnaire.. The mean baseline score of pain was approx 50% of most severe pain in all scoring systems. There was no significant decrease in pain associated with allopurinol compared to the placebo (p = 0.24-0.75). In addition, there was no benefit in terms of ADL score associated with allopurinol compared with placebo (p = 0.32). Mean uric acid level was decreased by 1.15 mg/dL while patients were taking allopurinol, compared to when they were taking placebo (p = 0.007).

Topics: Abdominal Pain; Activities of Daily Living; Adult; Allopurinol; Ankle; Blood Cell Count; Chronic Disease; Cross-Over Studies; Diarrhea; Double-Blind Method; Enzyme Inhibitors; Exanthema; Face; Female; Humans; Joints; Liver Function Tests; Male; Middle Aged; Nausea; Pain; Pain Measurement; Pancreatitis; Placebos; Prospective Studies; Uric Acid; Vomiting

The aim of this work was to assess the efficacy of itraconazole and allopurinol in chronic Chagas disease. Two hundred two subjects (137 infected, 59 with Chagas cardiopathy and 6 with non chagasic cardiopathy) were randomly assigned to be treated with itraconazole (87 subjects receiving 6 mg/kg/day for 120 days), allopurinol (68 subjects receiving 8.5 mg/kg/day for 60 days) or placebo (47 subjects during 60 days). Medications were well tolerated. Indirect hemagglutination test was modified in 5 subjects (3.2%) after treatment. Initially positive xenodiagnosis became negative in 34 of 36 subjects (94.4%) treated with itraconazole and 8 of 10 subjects (80%) treated with allopurinol. Initially normal EKG was not modified in 100% of patients receiving placebo, 84.9% receiving itraconazole and 86.7% receiving allopurinol. Initially abnormal EKG became normal in 10 of 31 subjects (32%) receiving itraconazole, 8 of 20 (40%) receiving allopurinol and none of 8 receiving placebo. It is concluded that xenodiagnosis and EKG improvements indicate that itraconazole and allopurinol have a role in the treatment of chronic Chagas disease. A 36 months follow up of these patients will help to confirm this conclusion.

Topics: Adolescent; Adult; Allopurinol; Chagas Disease; Child; Chronic Disease; Drug Resistance; Electrocardiography; Female; Follow-Up Studies; Humans; Itraconazole; Male; Middle Aged; Prognosis; Time Factors

This randomized double-blind trial examined the influence of the radical scavengers allopurinol (50 mg per rectum, four times per day) and dimethyl sulfoxide (500 mg per rectum, four times per day) on pancreatic pain treated with intramuscular pethidine hydrochloride (100 mg followed by 50 mg every 4 hours until complete pain relief) in patients given nothing orally and intravenously hydrated. Addition of allopurinol or dimethyl sulfoxide to the analgesic regimen significantly enhanced its efficacy, enabling at least 57% (13 patients receiving allopurinol and 12 patients receiving dimethyl sulfoxide) of 43 patients to be free of pain within 12 hours after admission compared with only four (17%) of 23 controls achieving the same effect. This advantage extended to all patients within 24 hours after admission, leaving 11 controls (48%) still in pain. Consequently, all patients given allopurinol or dimethyl sulfoxide were discharged 3 days after admission, a result realized in only five (22%) of the assessable controls who were discharged after 5 days of hospitalization. The results suggest that oxygen-derived free radicals are implicated in the mechanism of abdominal pain caused by alcohol-induced chronic pancreatitis and that removing them results in a beneficial therapeutic effect.

Topics: Abdominal Pain; Adult; Aged; Alcoholism; Allopurinol; Chronic Disease; Dimethyl Sulfoxide; Double-Blind Method; Drug Combinations; Female; Free Radicals; Humans; Male; Meperidine; Metoclopramide; Middle Aged; Oxygen; Pancreatitis; Prospective Studies; Recurrence; Time Factors

Laboratory and animal studies have demonstrated that pyrazolopyrimidines have significant activity against Trypanosoma cruzi. This clinical investigation was to ascertain the efficacy of allopurinol in the treatment of chronic Chagas' disease. Of 307 patients studied, 91 were untreated; the remaining 216 were divided into 4 treatment groups. These corresponded to 600 or 900 mg/day of allopurinol for 60 days and benznidazole or nifurtimox at conventional dosage regimens. Patients were evaluated clinically, serologically, and parasitologically. Allopurinol was found to be as efficacious as the conventional therapeutic modalities in eliminating the parasitemia and rendering patients seronegative. Adverse reactions occurred in 11% of patients who received allopurinol and in 30% of those receiving nitrofurans. Reactions with the conventional therapy were more frequent and of a more serious nature. Oral allopurinol is as effective as the nitrofurans, but has none of the side effects.

Topics: Adult; Allopurinol; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Topics: Allopurinol; Chagas Cardiomyopathy; Chagas Disease; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Nifurtimox; Nitroimidazoles; Trypanocidal Agents

Although an association of serum uric acid levels with endothelial function has been shown in various clinical settings, the optimal treatment target that would benefit vascular endothelial function has not been established. We, therefore, conducted a post hoc analysis of the Excited-UA study to identify an optimal target. Patients (N = 133) with chronic heart failure and comorbid hyperuricemia who enrolled in the Excited-UA study were divided into three tertiles based on their serum uric acid level 24 weeks after initiating xanthine oxidase inhibitor treatment with topiroxostat or allopurinol (i.e., groups with low, moderate, and high uric acid levels). Flow-mediated dilation (FMD) and reactive hyperemia index (RHI) values measured by reactive hyperemia peripheral arterial tonometry (RH-PAT) were compared among groups. The change from baseline in the FMD value 24 weeks after treatment was comparable among the three groups. In contrast, the change from baseline in the RHI was significantly different among the three groups (-0.153 ± 0.073, 0.141 ± 0.081 and -0.103 ± 0.104 in the low, moderate, and high uric acid level groups, respectively, P = 0.032). After adjustment for age, body mass index, and concomitant use of diuretics, which differed among the three groups, the change in the RHI in the moderate uric acid level group tended to be higher than that in the high uric acid level group (P = 0.057) and was significantly higher than that in the low uric acid level group (P = 0.020). These results indicate that targeting excessively low uric acid levels by treatment with xanthine oxidase inhibitors might be less beneficial for improving microvascular endothelial function in patients with chronic heart failure. Comparisons of the changes from baseline in vascular endothelial function parameters at 24 weeks among the 3 groups of low, moderae and high uric acid levels achieved with xanthine oxidase inhibitors. After adjustment for confounding factors, such as age, body mass index and concomitant diuretic use, which showed differences among the 3 groups, the change in RHI in the moderate uric acid level group tended to be higher than that in the high uric acid level group and was significantly higher than that in the low uric acid level group.

Topics: Chronic Disease; Diuretics; Endothelium, Vascular; Enzyme Inhibitors; Heart Failure; Humans; Hyperemia; Hyperuricemia; Uric Acid; Xanthine Oxidase

Topics: Adult; Allopurinol; Azathioprine; Chronic Disease; Dermatitis, Atopic; Drug Therapy, Combination; Eczema; Female; Foot Dermatoses; Guanine Nucleotides; Hand Dermatoses; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prospective Studies; Thionucleotides; Time Factors; Treatment Outcome

Topics: Allopurinol; Chronic Disease; Diet; Drug Combinations; Febuxostat; Gout; Gout Suppressants; Healthy Lifestyle; Humans; Patient Education as Topic; Practice Guidelines as Topic; Purines; Thioglycolates; Triazoles; Uric Acid

Topics: Aged; Allopurinol; Chronic Disease; Diagnosis, Differential; Gout; Gout Suppressants; Humans; Male

This study sought to observe the effects of allopurinol on the cardiac function of non-hyperuricaemic patients with chronic heart failure and determine the safety of allopurinol for clinical applications.. A group of 125 consecutive cases of non-hyperuricaemic patients with chronic heart failure who were treated at Chongqing Emergency Medical Centre between July 2011 and June 2012 were enrolled and were randomly divided into allopurinol (300 mg/day) group (n=62) and control group (n=63). During the six months treatment period, levels of cardiac function, brachial artery endothelial function, inflammatory cytokines, and biochemical markers were routinely examined.. After three months of allopurinol treatment, patients exhibited an increase in flow-mediated vasodilatation (FMD) of brachial artery, whereas, after six months of treatment, the cardiac function classification was improved; plasma levels of brain natriuretic peptide and tumour necrosis factor-a were decreased; left ventricular internal diameter was diminished; and the ejection fraction was increased (p<0.01 for all the parameters) in patients. Serum uric acid level was decreased during the treatment period for both groups, with no significant difference between the two groups. Liver and kidney dysfunction was not observed among the study participants, and no significant increase in creatine kinase level was detected for either treatment group.. For non-hyperuricaemic patients with chronic heart failure, the addition of six months of allopurinol therapy was safe and effective. Moreover, in these patients, allopurinol treatment not only can significantly ameliorate the left ventricular function and reduce the level of inflammatory factors but could also improve endothelial function.

Topics: Adult; Aged; Allopurinol; Biomarkers; Chronic Disease; Female; Follow-Up Studies; Heart Failure; Humans; Hyperuricemia; Male; Middle Aged; Natriuretic Peptide, Brain; Uric Acid; Vasodilation; Ventricular Function, Left

Gout is a chronic disease characterized by the deposition of urate crystals in the joints and throughout the body, caused by an excess burden of serum uric acid (sUA). The study estimates pharmacy and medical cost budgetary impacts of wider adoption by US payers of febuxostat, a urate-lowering therapy (ULT) for the treatment of gout.. A US payer-perspective budget impact model followed ULT patients from a 1,000,000-member plan over 3 years. The current market share scenario, febuxostat (6%) and ULT allopurinol (94%), was compared with an 18% febuxostat market share. Data were implemented from randomized controlled trials, census and epidemiologic studies, and real-world database analyses. An innovation was the inclusion of gout-related chronic kidney disease costs. Cost results were estimated as annual and cumulative incremental costs, expressed as total costs, cost per member per month, and cost per treated member per month. Clinical results were also estimated.. Increasing the febuxostat market share resulted in a 6.3% increase in patients achieving the sUA target level of <6.0 mg/dL and a 1.4% reduction in gout flares during the 3-year period. Total cost increased 1.4%, with a 49.9% increase in ULT costs, a 1.4% reduction in flare costs, a 1.2% reduction in chronic kidney disease costs, and a 2.8% reduction in gout care costs. The cumulative incremental costs were $1,307,425 in the first year, $1,939,016 through the second year, and $2,092,744 through the third year. By the third year, savings in medical costs offset most of the increase in treatment costs. Impacts on cumulative cost per member per month and cumulative cost per treated member per month followed the same pattern, with the highest impact in the first year and cumulative impacts declining during the 3-year period. The cumulative cost per member per month impact was estimated as $0.109, $0.081, and $0.058 and the cumulative cost per treated member per month impact was estimated as $12.416, $9.207, and $6.625 in the first year, through the second year, and through the third year, respectively.. Expanding the febuxostat market share would result in improved clinical outcomes, but with an overall increase in costs over 3 years due to higher costs of treatment. By the third year, savings in medical costs, primarily in chronic kidney disease costs, would offset most of the increase in treatment costs. Expanded use of febuxostat in the treatment of all gout patients, independent of renal impairment status, should be considered based on improved clinical outcomes and longer-term medical cost savings associated with these improved outcomes.

Topics: Adult; Aged; Allopurinol; Budgets; Chronic Disease; Febuxostat; Female; Gout; Gout Suppressants; Health Care Costs; Humans; Male; Managed Care Programs; Middle Aged; Pharmaceutical Services; Renal Insufficiency, Chronic; United States; Uric Acid; Young Adult

To determine the effect of the xanthine oxidase (XO) inhibitor allopurinol on myocardial energy metabolism in a chronic heart failure rat model after myocardial infarct.An AMI model was established in 6-week-old rats via the ligation of the anterior descending coronary artery. Thirty-five rats were randomly divided into the following 3 groups: an ALLO group, an AMI group, and a Sham group. Heart failure was successfully diagnosed via echocardiography and blood tests. Xanthine oxidase (XO), malondialdehyde (MDA), PGC-1α, CPT-1, and GLUT4 were monitored in the myocardium.The TEM results demonstrated that myofilament lysis and mitochondrial swelling were alleviated in the ALLO group compared with the AMI group (without ALLO). The results also demonstrated that cardiac function was significantly improved in the ALLO group compared with the AMI group. Compared with the AMI group, the ALLO group exhibited increased respiratory-chain enzyme activity, as well as increased PGC-1α and CPT-1 mRNA and protein expression, decreased MDA content, and decreased XO and GLUT4 mRNA and protein expression.ALLO improves myocardial energy metabolism in rats with chronic heart failure, which may result from the regulation of PGC-1α in the setting of glycolipid metabolism, enhancing the production of ATP.

Topics: Allopurinol; Animals; Chronic Disease; Disease Models, Animal; Energy Metabolism; Enzyme Inhibitors; Heart Failure; Male; Myocardial Infarction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

Topics: Allopurinol; Chronic Disease; Enzyme Inhibitors; Heart Failure; Humans; Xanthine Oxidase

Gout is a chronic inflammatory condition associated with poor urate metabolism. Xanthine oxidase inhibitors such as allopurinol and febuxostat are recommended to reduce uric acid levels and to prevent gout attacks in adult patients. Under budget-driven constraints, health care payers are faced with the broader challenge of assessing the economic value of these agents for formulary placement. However, the economic value of allopurinol versus febuxostat has not be assessed in patients with gout over a 5-year time period in the United States.. To evaluate the cost-effectiveness of allopurinol versus febuxostat in adult patients with gout over a 5-year time period from a U.S. health care payer's perspective.. A Markov model was developed to compare the total direct costs and success of serum uric acid (sUA) level reduction associated with allopurinol and febuxostat. Treatment success was defined as patient achievement of a sUA level less than  6 mg/dL (0.36 mmol/L) at 6 months. Event probabilities were based on published phase III randomized clinical trials and included long-term sequelae from open-label extension studies. A hypothetical cohort of 1,000 adult gout patients with sUA levels of ≥ 8 mg/dL (0.48 mmol/L) who had received either allopurinol 300 mg or febuxostat 80 mg at model entry transitioned among the 4 health states defined by treatment success, treatment failure and switch, treatment dropout, and death. The length of each Markov cycle was 6 months. Costs were gathered from the RED BOOK, Medicare fee schedules, Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, and for a limited number of inputs, expert consultation. Direct costs included treatment drug costs, costs for prophylaxis drugs, diagnostic laboratory tests, and the treatment and management of acute gout flare. Resource utilization was based on clinical evidence and expert consultation. All costs were inflated to 2014 U.S. dollars and were discounted at 3% in the base case. One-way sensitivity analysis and probabilistic sensitivity analyses (PSAs) were performed to assess the robustness of the results.. The total per patient cost incurred over 5 years was $50,295 for febuxostat and $48,413 for allopurinol, with an incremental total cost of $1,882. The expected percentage of treatment success during the 5-year period was 72 for febuxostat and 42 for allopurinol, resulting in an incremental percentage of treatment success of 30. The estimated incremental cost-effectiveness ratio for febuxostat compared with allopurinol was $6,322 per treatment success over a 5-year time period. The one-way sensitivity analysis indicated that the results were sensitive to probability of treatment success for allopurinol, probability of treatment dropouts for both allopurinol and febuxostat, and the probability of failure and switch to allopurinol. PSAs demonstrated that at a willingness-to-pay threshold of $50,000 per treatment success, febuxostat was cost-effective compared with allopurinol.. Febuxostat was found to be a cost-effective option compared with allopurinol based on a U.S. payer perspective.

Topics: Allopurinol; Chronic Disease; Cost-Benefit Analysis; Febuxostat; Gout; Gout Suppressants; Humans; Markov Chains; Thiazoles; Uric Acid

To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol treatment.. National prospective cohort study.. 15 medical centres in different regions of Taiwan, from July 2009 to August 2014.. 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants' peripheral blood was used to assess the presence of HLA-B*58:01.. Incidence of allopurinol induced SCARs with and without screening.. Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test).. Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.

Topics: Allopurinol; Chronic Disease; Drug Eruptions; Exanthema; Female; Genetic Testing; Genotype; Gout Suppressants; Heterozygote; HLA-B Antigens; Humans; Male; Middle Aged; Prospective Studies; Pruritus; Taiwan

The study objective was to determine the feasibility of using a pharmacist-staffed, protocol-based structured approach to improving the management of chronic, recurrent gout.. The study was carried out in the outpatient clinic of a single Kaiser Permanente medical centre. This is a community-based clinic.. We report on 100 consecutive patients between the ages of 21 and 94 (75% men) with chronic or recurrent gout, referred by their primary physicians for the purpose of management of urate-lowering therapy. Patients with stage 5 chronic kidney disease or end-stage kidney disease were excluded.. The programme consisted of a trained clinical pharmacist and a rheumatologist. The pharmacist contacted each patient by phone, provided educational and dietary materials, and used a protocol that employs standard gout medications to achieve and maintain a serum uric acid (sUA) level of 6 mg/dL or less. Incident gout flares or adverse reactions to medications were managed in consultation with the rheumatologist.. The primary outcome measure was the achievement and maintenance of an sUA of 6 or less for a period of at least 3 months.. In 95 evaluable patients enrolled in our pilot programme, an sUA of 6 mg/dL or less was achieved and maintained in 78 patients with 4 still in the programme to date. Five patients declined to participate after referral, and another 13 patients did not complete the programme. (The majority of these were due to non-adherence.). A structured pharmacist-staffed programme can effectively and safely lower and maintain uric acid levels in a high percentage of patients with recurrent gout in a primary care setting. This care model is simple to implement, efficient and warrants further validation in a clinical trial.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Ambulatory Care Facilities; Chronic Disease; Feasibility Studies; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Patient Care Planning; Pharmacy Service, Hospital; Pilot Projects; Treatment Outcome; Uric Acid

The role of hepatic tryptophan 2,3 dioxygenase (TDO) was assessed in the provocation of stress-induced depression-related behaviour in the rat. TDO drives tryptophan metabolism via the kynurenine pathway (KP) and leads to the production of neuroactive metabolites including kynurenine. A single 2 h period of restraint stress in adult male Sprague-Dawley rats provoked an increase in circulating concentrations of the glucocorticoid corticosterone and induction of hepatic TDO expression and activity. Repeated exposure to stress (10 d of 2 h restraint each day) provoked an increase in immobility in the forced swimming test (FST) indicative of depression-related behaviour. Immobility was accompanied by an increase in the circulating corticosterone concentrations, expression and activity of hepatic TDO and increase in the expression of TDO in the cerebral cortex. Increased TDO activity was associated with raised circulating kynurenine concentrations and a reduction in circulating tryptophan concentrations indicative of KP activation. Co-treatment with the TDO inhibitor allopurinol (20 mg/kg, i.p.), attenuated the chronic stress-related increase in immobility in the FST and the accompanying increase in circulating kynurenine concentrations. These findings indicate that stress-induced corticosterone and consequent activation of hepatic TDO, tryptophan metabolism and production of kynurenine provoke a depression-related behavioural phenotype. Inhibition of stress-related hepatic TDO activity promotes antidepressant activity. TDO may therefore represent a promising target for the treatment of depression associated with stress-related disorders in which there is evidence for KP activation.

Topics: Allopurinol; Animals; Antidepressive Agents; Cerebral Cortex; Chronic Disease; Corticosterone; Depressive Disorder; Disease Models, Animal; Enzyme Inhibitors; Kynurenine; Liver; Male; Neuropsychological Tests; Rats, Sprague-Dawley; Restraint, Physical; RNA, Messenger; Stress, Psychological; Tryptophan; Tryptophan Oxygenase; Weight Gain

Increased serum uric acid has been considered a cardiovascular risk factor but no study has assessed its relation with hospital mortality or length of stay. On the basis of data obtained from a prospective registry, the prevalence of gout/hyperuricemia and its association with these and other clinical parameters was evaluated in an Italian cohort of elderly patients acutely admitted to internal medicine or geriatric wards.. While the prevalence of gout was calculated by counting patients with this diagnosis hyperuricemia was inferred in patients taking allopurinol at hospital admission or discharge, on the assumption that this drug was only prescribed owing to the finding of high serum levels of uric acid. A series of clinical and demographic variables were evaluated for their association with gout/hyperuricemia.. Of 1380 patients, 139 (10%) had a diagnosis of gout or were prescribed allopurinol. They had more co-morbidities (7.0 vs 5.6; P<0.0001) and consumed more drugs (6.8 vs 5.0; P<0.0001). The CIRS (co-morbidity index) was worse in these patients (OR 1.28 95% CI 1.15-1.41). Multivariable regression analysis showed that only renal and heart failures were independently associated with gout/allopurinol intake. Moreover, this combined event was associated with an increased risk of adverse events during hospitalization (OR 1.66, 95% CI 1.16-2.36), but not with the risk of re-hospitalization, length of hospital stay or death.. Gout/allopurinol intake has a high prevalence in elderly patients acutely admitted to hospital and are associated with renal and cardiovascular diseases, an increased rate of adverse events and a high degree of drug consumption. In contrast, this finding did not affect the length of hospitalization nor hospital mortality.

Topics: Age Factors; Aged; Aged, 80 and over; Allopurinol; Cardiovascular Diseases; Chronic Disease; Comorbidity; Female; Gout; Hospital Mortality; Hospitalization; Humans; Hyperuricemia; Kidney Diseases; Length of Stay; Male; Treatment Outcome; Uric Acid

Chronic venous insufficiency (CVI) represents a social and health care problem because it affects working age populations, particularly in jobs requiring orthostasis, has no effective pharmacologic treatment, and requires surgery. Oxidative stress is present in varicose veins, but whether this is reflected in the plasma is controversial. We aimed to quantify plasma oxidative stress biomarkers in the early stages of CVI and calculate a global index of oxidative stress representative of the disease.. Plasma was obtained from blood samples of nine patients with CEAP C2 stage CVI and 10 healthy controls. Biomarkers related to antioxidant defense systems (total thiols, reduced glutathione, uric acid, total antioxidant capacity, catalase), oxidative damage (malondialdehyde-bound protein, protein carbonyls, advanced oxidation products, and 3-nitrotyrosine), and activity of enzymes producing key free radicals (xanthine oxidase and myeloperoxidase) were assessed.. Compared with the controls, CVI patients exhibited decreased catalase activity and thiol levels and increased malondialdehyde-bound protein and protein carbonyls. These parameters were used to calculate the global index of oxidative stress in CVI, which was significantly different between groups.. It is possible to detect significant changes in plasma oxidative stress biomarkers in early stages of CVI and to calculate a global index representative of the oxidative status in an individual. This index, with the appropriate validation in a larger population, could be used for early detection or progression of CVI.

Topics: Adult; Advanced Oxidation Protein Products; Biomarkers; Case-Control Studies; Catalase; Chronic Disease; Disease Progression; Early Diagnosis; Female; Glutathione; Humans; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Peroxidase; Predictive Value of Tests; Protein Carbonylation; Sulfhydryl Compounds; Tyrosine; Ultrasonography, Doppler, Color; Uric Acid; Veins; Venous Insufficiency; Xanthine Oxidase

To investigate the antioxidant activity of methanolic extracts of Lantana camara (L. camara) various parts and the determination of their total phenolics content.. The extract was screened for possible antioxidant activities by free radical scavenging activity(DPPH), xanthine oxidase inhibition activity and Griess-Ilosvay method.. The results showed that all the plant parts possessed antioxidant properties including radical scavenging, xanthine oxidase inhibition and nitrites scavenging activities. The antioxidative activities were correlated with the total phenol. The leaves extract of L. camara was more effective than that of other parts.. This study suggests that L. camara extracts exhibit great potential for antioxidant activity and may be useful for their nutritional and medicinal functions.

Topics: Allopurinol; Antioxidants; Chronic Disease; Free Radical Scavengers; Humans; Lantana; Methanol; Oxidation-Reduction; Oxidative Stress; Phenols; Phytotherapy; Plant Extracts; Plant Leaves; Plant Roots; Plant Stems; Plants, Medicinal; Reactive Oxygen Species; Solvents

Patients with chronic gout refractory to conventional urate-lowering therapy have high rates of flares and incidence of tophi, which impose a significant disease and potentially economic burden. This study examined healthcare resource use and costs stratified by disease burden. Adult patients diagnosed with gout (ICD-9-CM:274.xx) and having had ≥3 flares defined by clinical surrogates within a 12-month period were selected for the case cohort from the Thomson MarketScan databases (2003/Q3-2008/Q3). Only patients who had received allopurinol treatment and a diagnosis of tophi (ICD-9-CM:274.8x) at any time before the first flare (index date) or within 12 months postindex were included and were matched in a 1:1 ratio with control gout-free subjects. The comorbidity burden, healthcare resource use, and annual healthcare costs (2008 US$) in the 12-month postindex period were compared between both cohorts using regression models adjusted for demographic characteristic and stratified for patients with ≥6 flares. A total of 679 gout patients met the inclusion criteria for the study and had a higher prevalence of comorbidities than their matched controls. Gout cohort had a significantly higher incidence of emergency room, hospitalizations, outpatient visits, and other medical services than did their matched controls (all comparisons, uncorrected P < 0.01). After adjusting for baseline characteristics, the refractory gout cohort incurred an incremental total annual healthcare cost of $10,222 where 40% of the annual medical cost was for gout-related care compared with control cohort (P < 0.01). Patients with refractory gout have a significant economic burden compared with a gout-free population.

Topics: Adult; Allopurinol; Case-Control Studies; Chronic Disease; Cohort Studies; Comorbidity; Cost of Illness; Databases, Factual; Emergency Service, Hospital; Female; Gout; Gout Suppressants; Health Care Costs; Health Services; Hospitalization; Humans; Male; Middle Aged; Prevalence; Regression Analysis; Retrospective Studies

Chronic venous leg ulcers are a major health issue and represent an often overlooked area of biomedical research. Nevertheless, it is becoming increasingly evident that new approaches to enhance healing outcomes may arise through better understanding the processes involved in the formation of chronic wounds. We have for the first time shown that the terminal purine catabolite uric acid (UA) is elevated in wound fluid (WF) from chronic venous leg ulcers with relative concentrations correlating with wound chronicity. We have also shown a corresponding depletion in UA precursors, including adenosine, with increased wound severity. Further, we have shown that xanthine oxidase, the only enzyme in humans that catalyses the production of UA in conjunction with a burst of free radicals, is active in chronic WF. Taken together, this provides compelling evidence that xanthine oxidase may play a critical role in the formation of chronic wounds by prolonging the inflammatory process.

Topics: Aged; Blotting, Western; Chronic Disease; Exudates and Transudates; Humans; Leg Ulcer; Male; Middle Aged; Ultrafiltration; Uric Acid; Xanthine Oxidase

The aim of this work was to evaluate the hepatoprotective ability of allopurinol to prevent the liver injury induced by carbon tetrachloride (CCl(4)).. Acute liver damage was induced with CCl(4) (4g/kg, by gavage); allopurinol (50mg/kg, by gavage) was given 1h before and 1h after CCl(4) intoxication and two daily doses for the previous three days. Cirrhosis was established by CCl(4) administration (0.4g/kg, i. p. three times a week, eight weeks); allopurinol was administered (100mg/kg, by gavage, daily) during the long-term of CCl(4) treatment. Alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GTP), xanthine oxidase (XO), lipid peroxidation, reduced and oxidized glutathione (GSH, GSSG, respectively), hydroxyproline and histopathologycal analysis were performed. Nuclear factor-κB (NF-κB), pro-inflammatory and anti-inflammatory cytokines, transforming growth factor-β (TGF-β) and metalloproteinase-13 (MMP-13) were analyzed by Western blots.. Acute injury increased ALT and γ-GTP activities, additionally enhanced NF-κB nuclear translocation and cytokines production such as tumor necrosis factor-α, interleukine-1β, and interleukine-6. Allopurinol partially prevented these effects, while increased interleukine-10. Acute and chronic CCl(4) treatments altered the levels of XO activity, lipid peroxidation, and GSH/GSSG ratio, while these remained within normal range with allopurinol administration. Necrosis, fibrosis and TGF-β production induced in chronic injury were partially prevented by allopurinol, interestingly, this drug induced MMP-13 activity.. Allopurinol possesses antioxidant, anti-inflammatory and antifibrotic properties, probably by its capacity to reduce NF-κB nuclear translocation and TGF-β expression, as well as to induce MMP-13. General significance Allopurinol might be effective treatment of liver diseases.

Topics: Alanine Transaminase; Allopurinol; Animals; Blotting, Western; Carbon Tetrachloride; Cell Extracts; Cell Nucleus; Chronic Disease; Cytokines; gamma-Glutamyltransferase; Glutathione; Lipid Peroxidation; Liver; Liver Cirrhosis; Male; Matrix Metalloproteinase 13; NF-kappa B; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Xanthine Oxidase

Urate lowering therapy in this country has mainly been achieved by the use of allopurinol and probenecid. A new xanthine oxidase inhibitor called febuxostat has been approved in 2009 for treatment of hyperuricaemia in gout. In this report, we describe the management of a patient with chronic tophaceous gout using febuxostat. The reduction in serum uric acid to target levels was rapid, and the tophi size had also reduced significantly while on therapy. There was no unwanted side effect observed during the therapy. Therefore, febuxostat would be a useful alternative drug in the treatment of hyperuricaemia in gout patients who have contraindications to allopurinol and probenecid.

Topics: Allopurinol; Chronic Disease; Contraindications; Febuxostat; Gout; Gout Suppressants; Humans; Male; Middle Aged; Probenecid; Thiazoles

Gout is commonly undertreated and can lead to significant disability. Few data are available about the lived experience of gout or the barriers to effective urate-lowering therapy in men with gout.. This study aims to understand the experience of men living with chronic gout using a qualitative grounded theory approach.. Eleven English-speaking men with chronic gout participated in an in-depth semistructured interview about their experiences of living with gout. Interviews were recorded and transcribed. Consensus groups were used to analyze and validate the themes arising from the transcripts.. Three major themes related to the experience of gout emerged from the interviews: the impact of disease (pain, dependency on family members during flares, isolation, work disability), the progressiveness of untreated gout (increasing number of affected joints and frequency of flares, increase in food type triggers, escalating treatment required to control flares due to reducing efficacy of anti-inflammatory medication), and the lack of knowledge of gout (a community wide lack of understanding of the causes or prevention of gout, stoicism/tolerance to symptoms and disability, personal and social stigma related to gout).. Chronic gout has an important impact on both the patient and his family. This work provides previously hidden perspectives of the experience of gout, which may be generalized to other men with gout, suggesting that shame, embarrassment, and stigma lead to trivialization of the impact of disease despite its severity. These experiences may lead to undertreatment of gout because of lack of disclosure of symptom severity and lack of expectation of treatment effectiveness, which in turn could contribute to the development of progressive gout.

Topics: Adult; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Attitude to Health; Chronic Disease; Diet; Disease Progression; Exercise; Female; Gout; Gout Suppressants; Health Status; Humans; Male; Middle Aged; Pain Measurement; Qualitative Research; Quality of Life; Social Support

To determine if the association between hyperuricaemia and poor outcomes in heart failure (HF) varies by chronic kidney disease (CKD).. Of the 2645 systolic HF patients in the Beta-Blocker Evaluation of Survival Trial with data on baseline serum uric acid, 1422 had hyperuricaemia (uric acid ≥6 mg/dL for women and ≥8 mg/dL for men). Propensity scores for hyperuricaemia, estimated for each patient, were used to assemble a matched cohort of 630 pairs of patients with and without hyperuricaemia who were balanced on 75 baseline characteristics. Associations of hyperuricaemia with outcomes during 25 months of median follow-up were examined in all patients and in those with and without CKD (estimated glomerular filtration rate of <60 mL/min/1.73 m(2)). Hyperuricaemia-associated hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality and HF hospitalization were 1.44 (1.12-1.85, P = 0.005) and 1.27 (1.02-1.58, P = 0.031), respectively. Hazard ratios (95% CIs) for all-cause mortality among those with and without CKD were 0.96 (0.70-1.31, P = 0.792) and 1.40 (1.08-1.82, P = 0.011), respectively (P for interaction, 0.071), and those for HF hospitalization among those with and without CKD were 0.99 (0.74-1.33, P = 0.942) and 1.49 (1.19-1.86, P = 0.001), respectively (P for interaction, 0.033).. Hyperuricaemia has a significant association with poor outcomes in HF patients without CKD but not in those with CKD, suggesting that hyperuricaemia may predict poor outcomes when it is primarily a marker of increased xanthine oxidase activity, but not when it is primarily due to impaired renal excretion of uric acid.

Topics: Aged; Canada; Chronic Disease; Female; Glomerular Filtration Rate; Heart Failure; Hospitalization; Humans; Hyperuricemia; Kaplan-Meier Estimate; Kidney Diseases; Male; Middle Aged; Multicenter Studies as Topic; Prognosis; Propensity Score; Randomized Controlled Trials as Topic; United States; Xanthine Oxidase

Although there have been many studies on this topic, the molecular mechanism of the toxic effects of hyperammonemia on cells has not yet been fully explained. Recent studies have held oxidative stress mechanisms responsible for hyperammonemia-induced cell damage. Kidney functions are affected in diseases associated with an increase in ammonia in the blood. Our study tries to determine whether oxidative stress mechanisms are responsible for kidney damage in chronic hyperammonemia. We also investigated whether kidney damage is dependent on possible reactive oxygen products associated with the xanthine oxidase (XO) enzyme and whether the possible association can be inhibited with allopurinol, an XO enzyme inhibitor. The study took into consideration the enzyme activities of XO, xanthine dehydrogenase (XDH), superoxide dismutase (SOD), glutathione-S-transferase (GST), as well as protein thiol (P-SH) and malondialdehyde (MDA) levels. The data found demonstrated that chronic hyperammonemia had oxidative stress effects on the kidney, and that kidney XO and XDH activity changed. However, it was not possible to inhibit this oxidative stress in the kidney using allopurinol. Thus, we could not conclude that oxidative stress is an XO-dependent mechanism. The outcomes of the study suggested that this oxidative situation arising in hyperammonemia occurred through a mechanism other than the XO enzyme.

Topics: Allopurinol; Animals; Chronic Disease; Female; Free Radical Scavengers; Hyperammonemia; Kidney Diseases; Oxidative Stress; Rats; Rats, Wistar; Xanthine Oxidase

The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU ≥6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl. These patients were followed up once a month until the SU level remained at <6 mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 µmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100 µmol/l were required to achieve SU <6 mg/dl.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Arthritis, Gouty; Chronic Disease; Creatinine; Dose-Response Relationship, Drug; Drug Monitoring; Enzyme Inhibitors; Female; Gout; Gout Suppressants; Humans; Kidney Function Tests; Male; Middle Aged; Oxypurinol; Standard of Care; Uric Acid

Since the discovery of the inflammasome, interleukin 1 production has been found to be integral in the pathophysiology of gout. Interleukin 1 inhibition by Anakinra has been shown to effective for the treatment of gout. We report three cases of resistant chronic tophaceous gout who responded to anakinra subcutaneous injections on an intermittent basis.

Topics: Acute Disease; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Colchicine; Drug Resistance; Gout; Gout Suppressants; Humans; Injections, Subcutaneous; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Male; Middle Aged; Treatment Outcome

Topics: Allopurinol; Chronic Disease; Drug Discovery; Drug Utilization; Gout; Gout Suppressants; Guideline Adherence; Humans; Practice Guidelines as Topic; Practice Patterns, Physicians'; Probenecid

Exposure of newborn calves to chronic hypoxia causes pulmonary artery (PA) hypertension and remodeling. Previous studies showed that the redox-sensitive transcription factor, early growth response-1 (Egr-1), is upregulated in the PA of chronically hypoxic calves and regulates cell proliferation. Furthermore, we established in mice a correlation between hypoxic induction of Egr-1 and reduced activity of extracellular superoxide dismutase (EC-SOD), an antioxidant that scavenges extracellular superoxide. We now hypothesize that loss of EC-SOD in chronically hypoxic calves leads to extracellular superoxide-mediated upregulation of Egr-1. To validate our hypothesis and identify the signaling pathways involved, we utilized PA tissue from normoxic and chronically hypoxic calves and cultured calf and human PA smooth muscle cells (PASMC). Total SOD activity was low in the PA tissue, and only the extracellular SOD component decreased with hypoxia. PA tissue of hypoxic calves showed increased oxidative stress and increased Egr-1 mRNA. To mimic the in vivo hypoxia-induced extracellular oxidant imbalance, cultured calf PASMC were treated with xanthine oxidase (XO), which generates extracellular superoxide and hydrogen peroxide. We found that 1) XO increased Egr-1 mRNA and protein, 2) XO induced the phosphorylation of ERK1/2 and, 3) pretreatment with an ERK1/2 inhibitor prevented induction of Egr-1 by XO. siRNA knock-down of EC-SOD in human PASMC also upregulated Egr-1 mRNA and protein, activated ERK1/2, and enhanced SMC proliferation and reduced apoptosis. We conclude that an oxidant/antioxidant imbalance arising from loss of EC-SOD in the PA with chronic hypoxia induces Egr-1 via activation of ERK1/2 and contributes to pulmonary vascular remodeling.

Topics: Animals; Animals, Newborn; Apoptosis; Cattle; Cell Proliferation; Chronic Disease; Disease Models, Animal; Early Growth Response Protein 1; Extracellular Signal-Regulated MAP Kinases; Extracellular Space; Humans; Hypoxia; Male; MAP Kinase Signaling System; Mice; Myocytes, Smooth Muscle; Oxidation-Reduction; Oxidative Stress; Pulmonary Artery; Reactive Oxygen Species; RNA, Small Interfering; Superoxide Dismutase; Up-Regulation; Xanthine Oxidase

Obstructive sleep apnea is associated with left ventricular (LV) dysfunction, oxidant stress, and chronic intermittent hypoxia (CIH). Allopurinol (ALLO) is a xanthine oxidase inhibitor that also scavenges free radicals.. Using an animal model of CIH we hypothesized that ALLO decreases oxidant stress and cardiac injury.. Rats were exposed to either CIH (nadir 4-6%, approximately once per minute) or room air (handled controls, HC) for 8 h a day for 10 days. Four treatment groups (six to ten animals per group) were studied: CIH/ALLO, CIH/placebo (PLAC), HC/ALLO, and HC/PLAC. Outcomes included myocardial lipid peroxides (LPO) for oxidant stress, fraction shortening of the LV cavity for cardiac function (LVFS) and an assay for myocyte apoptosis.. LPO was lower in CIH/ALLO group compared to CIH/PLAC (179 +/- 102 vs. 589 +/- 68 mcg/mg protein, p < 0.05). LVFS was greater in ALLO animals than PLAC in both CIH and HC (CIH/ALLO 48.6 +/- 2.3% vs. CIH/PLAC 38 +/- 1.4%; HC/ALLO 64.9 +/- 1.8% vs. HC/PLAC 51.5 +/- 1.5%; both p < 0.05). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed fewer apoptotic nuclei in LV myocardium in CIH/ALLO compared to CIH/PLAC (38.0 +/- 1.4 vs. 48.6 +/- 2.3 positive nuclei per 2.5 mm(2) area, p < 0.05).. ALLO is associated with improvement in CIH-associated oxidant stress, myocardial dysfunction, and apoptosis in rats.

Topics: Allopurinol; Animals; Apoptosis; Chronic Disease; Disease Models, Animal; Free Radical Scavengers; Heart Diseases; Hypoxia; Oxidative Stress; Rats; Ventricular Dysfunction, Left

Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-beta (TGF-beta) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival.

Topics: Adenosine; Allopurinol; Animals; Anticoagulants; Azetidines; Base Sequence; Benzylamines; Chronic Disease; DNA Primers; Fibrosis; Glutathione; Humans; Insulin; Kidney; Kidney Transplantation; Male; Models, Animal; Organ Preservation; Organ Preservation Solutions; Oxidative Stress; Plasminogen Activator Inhibitor 1; Raffinose; RNA, Messenger; Signal Transduction; Swine; Temperature; Tissue Donors; Tissue Plasminogen Activator; Transforming Growth Factor beta; Transplantation, Autologous

An unusual picture of polyarticular tophaceous gout is reported. It concerns a 61-year-old patient with tophaceous deposits for 30 years. Descriptive clinical and radiographic images are furnished.

Topics: Allopurinol; Arthrography; Calcium Channel Blockers; Chronic Disease; Disease Progression; Elbow; Elbow Joint; Foot; Foot Deformities; Gout; Gout Suppressants; Hand; Humans; Joints; Magnetic Resonance Imaging; Male; Metacarpophalangeal Joint; Middle Aged; Patient Compliance; Sulfonamides

To identify gaps in therapy with urate-lowering drugs for the treatment of gout as well as factors associated with resuming therapy.. From 2 integrated delivery systems, we identified patients 18 years or older with a diagnosis of gout who initiated use of a urate-lowering drug from January 1, 2000 through June 30, 2006 and who had a gap in therapy. A gap was defined as a period of over 60 days after the completion of 1 prescription in which no refill for a urate-lowering drug was obtained. Survival curves were used to assess return to therapy of urate-lowering drugs. Cox proportional hazards analysis estimated the association between covariates and return to therapy.. There were 4166 new users of urate-lowering drugs (97% received allopurinol), of whom 2929 (70%) had a gap in therapy. Among those with a gap, in 75% it occurred in the first year of therapy. Fifty percent of patients with a gap returned to therapy within 8 months, and by 4 years it was 75%. Age 45-74 years (<45 referent) and greater duration of urate-lowering drug use before the gap was associated with resuming treatment within 1 year. In contrast, receipt of nonsteroidal anti-inflammatory drugs or glucocorticoids in the year before the gap was associated with a reduced likelihood of resuming therapy.. The majority of gout patients with gaps in urate-lowering drug use returned to treatment. More investigation is needed to better understand why patients may go for months without refilling prescriptions, given the clinical consequences of nonadherence.

Topics: Age Factors; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Chi-Square Distribution; Chronic Disease; Cohort Studies; Colchicine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Glucocorticoids; Gout; Gout Suppressants; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Patient Compliance; Probability; Proportional Hazards Models; Risk Assessment; Severity of Illness Index; Sex Factors; Time Factors; Treatment Outcome; Uric Acid

Why chronic gout, that is mostly a well diagnosed and controlled disease if it is timely and systematically treated with allopurinol, becomes a topical public health problem following 50 years after the introduction of pathogenetic therapy with xantine oxidase inhibitors is under consideration. The principles of rational therapy for chronic gouty arthritis are outlined.

Topics: Allopurinol; Chronic Disease; Diagnosis, Differential; Gout; Gout Suppressants; Humans; Xanthine Oxidase

Topics: Allopurinol; Angina Pectoris; Cardiovascular Agents; Chronic Disease; Enzyme Inhibitors; Humans; Trimetazidine; Vasodilator Agents

To enable clinicians to initiate appropriate steps for long-term management of gout, including controlling acute exacerbations and pain and sustaining target serum uric acid (SUA) levels to control hyperuricemia as the underlying metabolic disorder.. Incorporation of pertinent rheumatology and primary care literature seeking a comprehensive overview about the disease state of gout and its symptoms, comorbidities, and impact on quality of life, with a key focus on the role of serum uric acid, evidence-based approaches to long-term management of gout, and the importance of a functioning clinician-patient relationship.. Gout is increasingly recognized as a prevalent chronic disease state requiring appropriate long-term management while controlling for risk factors and comorbid conditions. Effective treatment options can help gout patients achieve therapeutic SUA targets to control gout flares and prevent potentially destructive disease manifestations. Patient education is an important element in achieving treatment goals and ensuring adherence.. Effective treatment plans for any gout patient must be guided by a long-term approach that focuses on sustained control of hyperuricemia, while providing continuous control of chronic disease. Patient education can be a key element in this process.

Topics: Acute Disease; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Gouty; Arthritis, Rheumatoid; Chronic Disease; Colchicine; Comorbidity; Disease Progression; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Male; Middle Aged; Patient Education as Topic; Quality of Life; Risk Factors; Thiazoles; Uric Acid; Uricosuric Agents; Xanthine Oxidase

Topics: Chronic Disease; Drug Approval; European Union; Febuxostat; Gout Suppressants; Humans; Hyperuricemia; Thiazoles; Xanthine Oxidase

An emerging theme in the study of the pathophysiology of persistent pain is the role of reactive oxygen species (ROS). In the present study, we examined the hypothesis that the exogenous supply of antioxidant drugs during peri-reperfusion would attenuate pain induced by ischemia/reperfusion (IR) injury. We investigated the analgesic effects of three antioxidants administered during peri-reperfusion using an animal model of complex regional pain syndrome-type I consisting of chronic post-ischemia pain (CPIP) of the hind paw.. Application of a tight-fitting tourniquet for a period of 3 h produced CPIP in male Sprague-Dawley rats. Low-dose allopurinol (4 mg/kg), high-dose allopurinol (40 mg/kg), superoxide dismutase (SOD, 4000 U/kg), N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), or SOD (4000 U/kg)+L-NAME (10 mg/kg) was administered intraperitoneally just after tourniquet application and at 1 and 2 days after reperfusion for 3 days. The effects of antioxidants in rats were investigated using mechanical and cold stimuli. Each group consisted of seven rats.. Allopurinol caused significant alleviation in mechanical and cold allodynia for a period of 4 weeks in rats with CPIP. Both SOD and L-NAME, which were used to investigate the roles of superoxide (O2(-)) and nitric oxide (NO) in pain, also attenuated neuropathic-like pain symptoms in rats for 4 weeks.. Our findings suggest that O2(-) and NO mediate IR injury-induced chronic pain, and that ROS scavengers administered during the peri-reperfusion period have long-term analgesic effects.

Topics: Allopurinol; Animals; Chronic Disease; Cold Temperature; Enzyme Inhibitors; Free Radical Scavengers; Ischemia; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase; Xanthine Oxidase

We report a case of Stevens-Johnson syndrome (SJS) caused by imatinib combined with allopurinol. An 82-year-old female patient who had a diagnosis of chronic myeloid leukemia was initially treated with imatinib 200 mg/day and allopurinol 100 mg for 42 days, and had a satisfactory hematological response. The dose of imatinib was adjusted to 400 mg/day for 14 days. After two weeks, she developed SJS and was transferred to the intensive care unit for further treatment because her general condition had deteriorated. The aggravated cutaneous adverse reaction improved approximately 7 days after withdrawal of imatinib. Oral steroids with antihistamines were prescribed for the treatment of severe cutaneous reaction. The symptoms of SJS completely improved 1 month after discontinuation of imatinib and allopurinol. We concluded that imatinib alone may cause serious cutaneous reaction, but the combination of 2 high-risk drugs may increase the likelihood of exposed patients developing SJS. Physicians should be aware of the possibility of SJS caused by imatinib and allopurinol prescribed simultaneously.

Topics: Aged, 80 and over; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Chronic Disease; Female; Humans; Imatinib Mesylate; Kidney Failure, Chronic; Leukemia, Myeloid; Piperazines; Pyrimidines; Stevens-Johnson Syndrome

To examine whether markers of oxidative stress differ as a function of Type D personality, depression, and chronic heart failure (CHF) etiology. Type D (distressed) personality and depression are related to poor cardiac prognosis. Because patients with CHF are characterized by increased oxidative stress, this may be a candidate mechanism responsible for the adverse prognosis in emotionally distressed patients with CHF.. Serum levels of xanthine oxidase (XO), inducible heat shock protein (Hsp)70, and deoxyribonucleic acid damage marker 8-OHdG were measured in 122 patients, and effects of Type D, depression, and etiology were assessed.. CHF patients with Type D personality had lower levels of Hsp70 than non-Type D patients (6.48 ng/mL versus 7.85 ng/mL, p = .04, d = 0.26), and in case of an ischemic etiology, higher levels of XO (13.57 ng/mL versus 9.84 ng/mL, p = .01, d = 0.98). There were no significant univariate differences for depression. When adding depression as an additional independent variable in the Type D analysis, the effect of Type D personality remained significant (F = 5.460, p = .02) and was independent of depression (F = 0.942, p = .33). The ratio of XO to Hsp70 was significantly higher in Type D patients with CHF as compared with non-Type D patients (6.14 versus 2.83, p = .03, d = 0.39), independent of etiology class.. CHF patients with Type D personality are characterized by an increased oxidative stress burden, apparent in the decreased antioxidant levels and an increased oxidative stress ratio.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Chronic Disease; Comorbidity; Deoxyguanosine; Depressive Disorder, Major; DNA Damage; Enzyme-Linked Immunosorbent Assay; Female; Health Status; Heart Failure; HSP72 Heat-Shock Proteins; Humans; Male; Myocardial Infarction; Oxidative Stress; Personality; Personality Inventory; Risk Factors; Stress, Psychological; Xanthine Oxidase

The aim of this study was to ascertain the management of gout by doctors in Malaysia.. A cross-sectional questionnaire survey was carried out among doctors attending rheumatology post-graduate courses, where gout was not a lecture topic.. A total of 128 questionnaires were analyzed, of which the majority (67: 52.3%) were general practitioners. In the treatment of acute gout, 68.0% use non-selective non-steroidal anti-inflammatory drugs (NSAIDs), 53.9% use selective COX-2 inhibitors (coxibs), 66.4% use colchicine and 10.2% use allopurinol (ALLO). In the treatment of chronic gout, 36.7% use NSAIDs, 44.5% use coxibs, 19.5% use colchicine and 93% use ALLO. In both acute and chronic gout, corticosteroids (CS) are not used by over 90% of respondents. Fifty percent would stop ALLO during an acute attack. 95.3% do not start ALLO during an acute attack; 87.5% would start ALLO after the attack, with a median of 14 days afterwards. Once ALLO was started, 54.7% would continue indefinitely. Regarding target urate levels while on treatment, 10.9% would be satisfied with a high normal range, 21.9% middle of the range, 18.0% low normal range and 45.3% anywhere within the normal range. Fifteen percent would treat asymptomatic hyperuricemia.. In Malaysia, anti-inflammatory agents are most commonly used for the treatment of acute and chronic gout, with corticosteroid usage at a low level. However, there are areas of concern regarding the diagnosis of gout and the usage of ALLO which are not consistent with current guidelines.

Topics: Acute Disease; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Colchicine; Cross-Sectional Studies; Cyclooxygenase 2 Inhibitors; Glucocorticoids; Gout; Gout Suppressants; Humans; Malaysia; Primary Health Care; Professional Practice; Reference Values; Surveys and Questionnaires; Uric Acid

Uric acid (UA) is the end product of purine metabolism in humans. Hyperuricemia is often found in patients with chronic heart failure (CHF). The increase of serum UA level is inversely associated with disease severity, cardiac function and prognosis of CHF. Some researchers found that UA had detrimental impact on the cardiovascular system, including mediating immune response upon cell injury, increasing endotoxin-stimulated tumor necrosis factor-alpha production and hence proinflammatory immune activation, increasing blood pressure, and so on. Other researchers found that UA had important antioxidant properties by scavenging various reactive oxygen species. So far, there is no evidence suggest that UA has detrimental effect on the pathophysiology of CHF. Xanthine oxidase (XO) is an enzyme that produces uric acid during purine metabolism. XO activity is up-regulated in failing heart, and serum UA levels reflect the degree of XO activation in CHF. XO plays an important role in the pathophysiology process of CHF, including myocyte apoptosis, endothelial dysfunction and cardiac mechanoenergetic uncoupling. The therapeutic effect of long-term XO inhibition has been confirmed in animal models and partly in human bodies. We hypothesize that UA itself is not a player but a bystander associated with the activation of XO in the pathophysiology of CHF.

Topics: Chronic Disease; Endothelium, Vascular; Heart Failure; Humans; Hyperuricemia; Uric Acid; Xanthine Oxidase

Xanthine oxidase (XO)-derived reactive oxygen species (ROS) formation contributes to experimental chronic hypoxic pulmonary hypertension in adults, but its role in neonatal pulmonary hypertension has received little attention. In rats chronically exposed to hypoxia (13% O(2)) for 14 days from birth, we examined the effects of ROS scavengers (U74389G 10 mg.kg(-1).day(-1) or Tempol 100 mg.kg(-1).day(-1) ip) or a XO inhibitor, Allopurinol (50 mg.kg(-1).day(-1) ip). Both ROS scavengers limited oxidative stress in the lung and attenuated hypoxia-induced vascular remodeling, confirming a critical role for ROS in this model. However, both interventions also significantly inhibited somatic growth and normal cellular proliferation in distal air spaces. Hypoxia-exposed pups had evidence of increased serum and lung XO activity, increased vascular XO-derived superoxide production, and vascular nitrotyrosine formation. These changes were all prevented by treatment with Allopurinol, which also attenuated hypoxia-induced vascular remodeling and partially reversed inhibited endothelium-dependent arterial relaxation, without affecting normal growth and proliferation. Collectively, our findings suggest that XO-derived superoxide induces endothelial dysfunction, thus impairing pulmonary arterial relaxation, and contributes to vascular remodeling in hypoxia-exposed neonatal rats. Due to the potential for adverse effects on normal growth, targeting XO may represent a superior "antioxidant" strategy to ROS scavengers for neonates with pulmonary hypertension.

Topics: Acetylcholine; Allopurinol; Animals; Animals, Newborn; Cell Proliferation; Chronic Disease; Cyclic N-Oxides; Dinoprost; Free Radical Scavengers; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Nitric Oxide Synthase Type III; Organ Size; Oxidative Stress; Pregnatrienes; Pulmonary Artery; Rats; Reactive Oxygen Species; Spin Labels; Superoxides; Time Factors; Xanthine Oxidase

Chronic hypoxic (CH) preconditioning reduces superoxide-induced renal dysfunction via the upregulation of superoxide dismutase (SOD) activity and contents. Endotoxaemia reduces renal antioxidant status. We hypothesize that CH preconditioning might protect the kidney from subsequent endotoxaemia-induced oxidative injury. Endotoxaemia was induced by intraperitoneal injection of lipopolysaccharide (LPS; 4 mg kg(-1)) in rats kept at sea level (SL) and rats with CH in an altitude chamber (5500 m for 15 h day(-1)) for 4 weeks. LPS enhanced xanthine oxidase (XO) and gp91phox (catalytic subunit of NADPH oxidase) expression associated with burst amount of superoxide production from the SL kidney surface and renal venous blood detected by lucigenin-enhanced chemiluminescence. LPS induced a morphologic-independent renal dysfunction in baseline and acute saline loading stages and increased renal IL-1beta protein and urinary protein concentration in the SL rats. After 4 weeks of induction, CH significantly increased Cu/ZnSOD, MnSOD and catalase expression (16 +/- 17, 128 +/- 35 and 48 +/- 21, respectively) in renal cortex, and depressed renal cortex XO (44 +/- 16%) and renal cortex (20 +/- 9%) and medulla (28 +/- 11%) gp91phox when compared with SL rats. The combined effect of enhanced antioxidant proteins and depressed oxidative proteins significantly reduced LPS-enhanced superoxide production, renal XO and gp91phox expression, renal IL-1beta production, and urinary protein level. CH also ameliorated LPS-induced renal dysfunction in the baseline and acute saline loading periods. We conclude that CH treatment enhances the intrarenal antioxidant/oxidative protein ratio to overcome endotoxaemia-induced reactive oxygen species formation and inflammatory cytokine release.

Topics: Acclimatization; Altitude; Animals; Catalase; Chronic Disease; Disease Models, Animal; Endotoxemia; Female; Glomerular Filtration Rate; Hypoxia; Interleukin-1beta; Kidney; Lipopolysaccharides; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Proteinuria; Rats; Rats, Wistar; Renal Circulation; Sodium Chloride; Superoxide Dismutase; Superoxides; Xanthine Oxidase

Topics: Acclimatization; Altitude; Animals; Catalase; Chronic Disease; Disease Models, Animal; Endotoxemia; Glomerular Filtration Rate; Hypoxia; Interleukin-1beta; Kidney; Lipopolysaccharides; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Proteinuria; Rats; Renal Circulation; Sodium Chloride; Superoxide Dismutase; Superoxides; Xanthine Oxidase

Topics: Adult; Allopurinol; Antipsychotic Agents; Chronic Disease; Clozapine; Drug Therapy, Combination; Female; Gout; Gout Suppressants; Hallucinations; Humans; Piperazines; Psychoses, Substance-Induced; Recurrence; Schizophrenia, Paranoid; Thiazoles

To assess concordance of the management of chronic gout in UK primary care with the European League Against Rheumatism (EULAR) gout recommendations.. A postal questionnaire was sent to all adults aged >30 years registered with two general practices. Patients with possible gout attended for clinical assessment, at which the diagnosis was verified clinically. Aspects of chronic gout management, including provision of lifestyle modification advice, use of urate-lowering therapies (ULT) including dose titration to serum urate (SUA) level, prophylaxis against acute attacks, and diuretic cessation were assessed in accordance with the EULAR recommendations.. Of 4249 (32%) completed questionnaires returned, 488 reported gout or acute attacks and were invited for clinical assessment. Of 359 attendees, 164 clinically confirmed cases of gout were identified. Advice regarding alcohol consumption was recalled by 59 (41%), weight loss by 36 (25%) and diet by 42 (29%). Allopurinol was the only ULT used and was taken by 44 (30%); 31 (70%) were taking 300 mg daily. Mean SUA was lower in allopurinol users than non-users (318 vs 434 micromol/l) and was less often >360 micromol/l in allopurinol users (23% vs 75%). Eight patients had recently commenced allopurinol; two of these also were taking prophylactic colchicine or non-steroidal anti-inflammatory drugs. Of 25 patients with diuretic-induced gout, 16 (64%) were still taking a diuretic.. Treatment of chronic gout is often suboptimal and poorly concordant with EULAR recommendations. Lifestyle advice is infrequently offered, and allopurinol is restricted to a minority. Persistent hyperuricaemia was often seen in allopurinol non-users, but was also in allopurinol users, suggesting that doses >300 mg are often necessary.

Topics: Adult; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Colchicine; Diuretics; England; Family Practice; Female; Gout; Gout Suppressants; Humans; Kidney Diseases; Male; Middle Aged; Practice Guidelines as Topic; Uric Acid; Uricosuric Agents

To record practice patterns of treatment of acute gout in hospitalized patients.. We performed a retrospective chart review of hospitalized patients diagnosed with gout.. Seventy-nine (43%) patients were diagnosed with acute gout during their hospitalization. Fifty-eight (73%) patients with acute gout were found to have a reduction in their glomerular filtration rate. Twenty patients (25%) underwent arthrocentesis. The most widely used drugs for acute gout were colchicine, n = 42 (53%), and nonsteroidal antiinflammatory drugs (NSAID), n = 40 (51%). Combination therapy was used in 52% of patients with acute gout. Thiry-six (86%) patients treated with colchicine and 32 (80%) patients treated with NSAID had renal failure.. Crystal analysis, the gold standard for diagnosing gout, was performed in only 25% of patients suspected of acute gout. Combination antiinflammatory agents are used in over 50% of patients despite the absence of evidence to support use of such combinations. Renal failure was present in 73% of patients with acute gout. Colchicine and NSAID should therefore be used with caution in these patients. Practice patterns vary widely and often appear to be in conflict with recommended diagnostic and treatment measures for acute gout.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Colchicine; Drug Therapy, Combination; Gout; Gout Suppressants; Hospitalization; Humans; Male; Middle Aged; Practice Patterns, Physicians'; Renal Insufficiency; Retrospective Studies

Topics: Aged; Allopurinol; Chronic Disease; Female; Gout; Humans; Kidney Transplantation; Osteoarthritis; Prednisone; Risk Factors; Ultrasonography

Allopurinol dosage reduction is recommended in patients with renal dysfunction because drug toxicity risk is increased. Little information is available about serum creatinine (SCr) monitoring in ambulatory patients taking allopurinol.. To evaluate SCr monitoring among patients prescribed allopurinol, identify associated factors, and evaluate administrative data in assessing monitoring.. Information for this retrospective cohort study was drawn from a dataset of 2 020 037 individuals; approximately 200 000 members from each of 10 organizations. Study patients had received at least one year of ongoing allopurinol prescription dispensings. Patient variables analyzed included age, gender, chronic diseases, outpatient visits, hospitalizations, gout diagnosis, and SCr monitoring. A random sample of medical records was reviewed to assess the accuracy of the automated data. Statistical analysis included descriptive and logistic regression techniques.. Overall, 1139 (26%) of 4357 patients did not have SCr monitoring. For individuals without recent hospitalization, factors protective against lack of monitoring were increasing age (OR 0.77 per 10 y; 95% CI 0.74 to 0.79), more chronic diseases (OR 0.81; 95% CI 0.78 to 0.83), more outpatient visits (OR 0.87 per 5 visits; 95% CI 0.83 to 0.91), and gout diagnosis (OR 0.74; 95% CI 0.65 to 0.85). The sensitivity and specificity of administrative data compared with medical records for SCr monitoring were 92% and 65%, respectively.. More than one-fourth of patients dispensed allopurinol did not have SCr monitoring during one year of therapy. Lack of monitoring and lack of subsequent possible dosage adjustment put patients at increased risk of allopurinol toxicity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Chronic Disease; Cohort Studies; Creatinine; Databases, Factual; Female; Gout Suppressants; Health Maintenance Organizations; Humans; Insurance, Health; Male; Middle Aged; Monitoring, Physiologic; Retrospective Studies

Although drug induced interstitial nephritis is a relatively common cause of renal failure,granulomatous forms remain a rare condition. The development of a chronic granulomatous interstitial nephritis due to allopurinol is exceptional, only three cases have been described previously. We report on a patient who presented a granulomatous interstitial nephritis after 10 years of allopurinol administration (300 mg/day). At diagnosis, he had end stage renal disease and dialysis treatment was needed. Two months after drug withdrawal and on corticoid treatment a slow recovery of renal function was observed, allowing the interruption of dialysis. Two years after, the creatinine clearance is 23 ml/min,being dialysis free. We discuss the differential diagnosis of granulomatous interstitial nephritis and its rare association with allopurinol treatment.

Topics: Adrenal Cortex Hormones; Aged; Allopurinol; Chronic Disease; Creatinine; Diagnosis, Differential; Granuloma; Humans; Hyperuricemia; Kidney Failure, Chronic; Male; Nephritis, Interstitial; Renal Dialysis; Sarcoidosis

A substantial body of evidence has accumulated to suggest a role for the xanthine oxidase metabolic pathway in the pathophysiology of chronic heart failure and other cardiovascular diseases.

Topics: Allopurinol; Cardiac Output, Low; Chronic Disease; Enzyme Inhibitors; Exercise Tolerance; Humans; Oxygen Consumption; Xanthine Oxidase

Topics: Allopurinol; Anti-Inflammatory Agents; Benzbromarone; Chronic Disease; Colchicine; Drug Hypersensitivity; Gout; Humans; Uric Acid; Uricosuric Agents

Eleven years after they had been given itraconazole or allopurinol for the treatment of chronic American trypanosomiasis, 109 adult patients were checked for electrocardiographic abnormalities and evidence of Trypanosoma cruzi infection. The parasitological investigations included xenodiagnosis, in which the faeces of Triatoma infestans that had fed on the patients were checked under the microscope for flagellates. In addition, a PCR-based assay and a hybridization assay were used to test blood samples from the patients, and faeces from the Tri. infestans that had fed on the patients, for Try. cruzi DNA. For the data analysis, the patients were divided into four groups known as normal/normal, abnormal/normal, normal/abnormal and abnormal/abnormal, according to whether the patients had been found to have normal or abnormal electrocardiograms (ECG) shortly before the first treatment and to have normal or abnormal ECG when checked at the 11-year follow-up. The 51 normal/normal and 24 normal/abnormal patients were assumed to have been in the 'indeterminate' phase of the disease when they were treated, whereas the 16 abnormal/normal and 18 abnormal/abnormal patients all had evidence of chagasic cardiopathy at that time. When checked 11 years post-treatment, 40 (78.4%), 17 (70.8%), 14 (87.5%) and 17 (94.4%) of these patients, respectively, were each found positive for Try. cruzi in at least one of the parasitological tests. The hybridization assay, whether applied to human blood or bug faeces, appeared a significantly more sensitive test than the PCR-based assays or microscopically assessed xenodiagnosis (P<0.05). Only the 21 patients who appeared to be negative for Try. cruzi could be considered parasitologically cured (although all still appeared to have anti-Try. cruzi antibodies in their blood). Only 13 of these parasitologically cured patients (seven of those treated with itraconazole and six of those given allopurinol) had normal ECG at the 11-year follow-up. In Chile at least, itraconazole, which caused fewer adverse effects than the allopurinol while being no less effective at preventing cardiopathy, appears to be the drug of choice to treat chronic American trypanosomiasis in adults.

Topics: Adult; Allopurinol; Animals; Arrhythmias, Cardiac; Chagas Disease; Chronic Disease; DNA, Protozoan; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Itraconazole; Male; Middle Aged; Polymerase Chain Reaction; Trypanosoma cruzi; Xenodiagnosis

The presence of Trypanosoma cruzi in chronic chagasic patients with negative xenodiagnosis (XD) after 6 years following completion of therapy with either itraconazole or allopurinol was assessed by polymerase chain reaction (PCR) and hybridization assays. A 330-bp DNA fragment amplified from the hypervariable regions of T. cruzi kinetoplastid minicircles was hybridized with total 32P-labeled kinetoplast DNA as probes. PCR alone enabled the identification of T. cruzi nucleotide sequences in 40% of the patients treated with itraconazole and in 60% of patients treated with allopurinol. PCR used in combination with hybridization detected parasite DNA in 60% and 53% of XD negative individuals treated with itraconazole or allopurinol, respectively. These results show that PCR and hybridization are more sensitive than conventional parasitological techniques in diagnosing patients that have undergone chemotherapy with itraconazole or allopurinol.

Topics: Adult; Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Chronic Disease; Female; Humans; Itraconazole; Male; Nucleic Acid Hybridization; Polymerase Chain Reaction; Trypanosoma cruzi

Serum uric acid (UA) could be a valid prognostic marker and useful for metabolic, hemodynamic, and functional (MFH) staging in chronic heart failure (CHF).. For the derivation study, 112 patients with CHF (age 59+/-12 years, peak oxygen consumption [Vo2] 17+/-7 mL/kg per minute) were recruited. In separate studies, we validated the prognostic value of UA (n=182) and investigated the relationship between MFH score and the decision to list patients for heart transplantation (n=120). In the derivation study, the best mortality predicting UA cutoff (at 12 months) was 565 micromol/L (9.50 mg/dL) (independently of age, peak Vo2, left ventricular ejection fraction, diuretic dose, sodium, creatinine, and urea; P<0.0001). In the validation study, UA >or=565 micromol/L predicted mortality (hazard ratio, 7.14; P<0.0001). In 16 patients (from both studies) with UA >or=565 micromol/L, left ventricular ejection fraction

Topics: Biomarkers; Chronic Disease; Comorbidity; Female; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Hyperuricemia; Male; Middle Aged; Models, Statistical; Oxygen Consumption; Predictive Value of Tests; Prognosis; Risk Factors; ROC Curve; Sensitivity and Specificity; Stroke Volume; Survival Rate; Uric Acid; Xanthine Oxidase

A rabbit model of chronic ileitis has helped decipher the mechanism of alteration of multiple electrolyte and nutrient malabsorptions in inflammatory bowel disease (IBD). This study examined alterations in the adenosine A1/A3 receptor, oxidant, antioxidant, and immune-inflammatory pathways in chronic ileitis. Chronic ileal inflammation was induced 13-15 days after infection with 10,000 Eimeria magna oocytes. Quantitative analysis in 16 rabbits was done for oxidants, antioxidants, A1 and A3 transcripts, transport, injury, and inflammatory mediators. Inflamed gut had villus blunting, crypt hyperplasia and fusion, and immune cell infiltration. Alkaline phosphatase and Na-glucose co-transport were reduced by 78% (P=0.001) and 89% (P=0.001), respectively. Real-time fluorescence monitoring (TaqMan)-polymerase chain reaction revealed a transcriptional up-regulation of 1.34-fold for A1 and 5.40-fold for A3 receptors in inflamed gut. Lipid peroxidation increased in the mucosa (78%, P=0.012), longitudinal muscle-myenteric plexus (118%, P=0.042), and plasma (104%, P=0.001). Mucosal antioxidants were altered by inflammation: reductions occurred in superoxide dismutase (32%, P=0.001) and catalase (43%, P=0.001), whereas increases occurred in glutathione (75%, P=0.0271) and glutathione reductase (86%, P=0.0007). Oxidant enzyme activities were elevated by 21% for xanthine oxidase (P=0.004), 172% for chloramine (P=0.022), 47% for gelatinase (P=0.041), and 190% for myeloperoxidase (P=0.002). Mast cell tryptase increased by 79% (P=0.006). Increases occurred in the plasma concentration of leukotriene B(4) (13-fold, P=0.003), thromboxane B(2) (61-fold, P=0.018), and tumor necrosis factor-alpha (9-fold, P=0.002). In conclusion, chronic ileitis and tissue injury are associated with discrete alterations in complex multi-level oxidant, antioxidant, and immune inflammatory components. The rabbit ileitis model is a suitable model to gain further insight into chronic inflammation and IBD. We hypothesize that adenosine A3 and A1 receptors may provide a novel target for therapy in chronic ileitis and perhaps IBD.

Topics: Animals; Antioxidants; Chronic Disease; Disease Models, Animal; Free Radicals; Gelatinases; Ileitis; Inflammation; Intestinal Mucosa; Lipid Peroxidation; Male; Oxidative Stress; Rabbits; Receptor, Adenosine A3; Receptors, Purinergic P1; RNA, Messenger; Serine Endopeptidases; Tryptases; Up-Regulation; Xanthine Oxidase

Renal ischaemia releases reactive oxygen species (ROS) in the kidneys. We hypothesized that the kidneys are more resistant to the insult of ROS in chronically hypoxic rats. We thus compared rats kept at sea level (SL) and those that had been adapted to hypoxia (hypoxia adapted, HA) by exposure to an altitude of 5500 m in an altitude chamber for 15 h day-1 for 4 weeks. Xanthine (X, 0.75 mg kg-1) and xanthine oxidase (XO, 24.8 mU kg-1) were injected intrarenally. A lucigenin-enhanced chemiluminescence method was employed to detect the amount of free radicals in renal venous blood samples and on the kidney surface. In the renal venous blood samples, 26.05 (+/- 4.36) x 104 and 10.98 (+/- 1.79) x 104 counts were detected in the SL and HA rats, respectively, after X-XO treatment; these figures were significantly different. On the kidney surface of the SL rats, the free radical count amounted to 12.77 (+/- 1.64) x 104, while that in the HA rats was 8.47 (+/- 0.42) x 104; these figures were also significantly different. There was a significant increase in urine volume and urinary excretion of Na+, K+ and protein after X-XO administration in both groups of rats. However, the effect was greater for the SL rats than for the HA rats. The lipid peroxidation of the kidneys was not significantly different in the two groups of rats. Finally, we found that the activity of superoxide dismutase (SOD) and SOD mRNA were higher in the renal tissue of HA rats. We conclude that the renal response to free radicals is attenuated after chronic hypoxia in rats, and that SOD might play an important role in protecting HA rats from oxidative stress.

Topics: Altitude; Animals; Antioxidants; Chronic Disease; Female; Hematocrit; Hypoxia; Isoprostanes; Kidney; Kidney Function Tests; Lipid Peroxidation; Malondialdehyde; Rats; Rats, Wistar; Reactive Oxygen Species; Renal Circulation; RNA, Messenger; Superoxide Dismutase; Xanthine Oxidase

Topics: Adult; Allopurinol; Benzbromarone; Chronic Disease; Drug Therapy, Combination; Gout; Gout Suppressants; Humans; Male; Uricosuric Agents

To examine whether allopurinol is associated with any alteration in mortality and hospitalisations in patients with chronic heart failure (CHF). This hypothesis is based on previous data that a high urate concentration is independently associated with mortality with a risk ratio of 4.23 in CHF.. Retrospective cohort study.. Medicines Monitoring Unit, Ninewells Hospital, Dundee, UK.. 1760 CHF patients divided into four groups: those on no allopurinol, those on long term low dose allopurinol, those on short term low dose allopurinol, and those on long term high dose allopurinol.. Total mortality, cardiovascular mortality, cardiovascular hospitalisations, cardiovascular mortality or hospitalisations.. Long term low dose allopurinol was associated with a significant worsening in mortality over those who never received allopurinol (relative risk 2.04, 95% confidence interval (CI) 1.48 to 2.81). This may be because low dose allopurinol is insufficient to negate the adverse effect of a high urate concentration. However, long term high dose (> or = 300 mg/day) allopurinol was associated with a significantly better mortality than longstanding low dose allopurinol (relative risk 0.59, 95% CI 0.37 to 0.95). This may mean that high dose allopurinol can fully negate the adverse effect of urate and return the mortality to normal.. Long term high dose allopurinol may be associated with a better mortality than long term low dose allopurinol in patients with CHF because of a dose related beneficial effect of allopurinol against the well described adverse effect of urate. Further work is required to substantiate or refute this finding.

Topics: Aged; Allopurinol; Cardiac Output, Low; Chronic Disease; Cohort Studies; Female; Free Radical Scavengers; Gout Suppressants; Hospitalization; Humans; Male; Mortality; Proportional Hazards Models; Regression Analysis; Retrospective Studies; Survival Analysis; Treatment Outcome

The typical form of acute gout can be clinically diagnosed. The term 'complicated gout' is used if there are more than three acute attacks of gout per year, tophi or urate stones in the urinary tracts. In the case of recurrent probable acute gout, a diagnostic fine needle aspirate from the joint during an attack is indicated. First choice treatment of acute gout consists of NSAIDs. Colchicine is the second choice treatment and the third choice treatment consists of corticosteroids. Excessive alcohol use should be limited. Treatment of chronic gout depends on the uric acid excretion in the 24-hour urine. If the level of excretion is too low, the first choice should be benzbromarone, and if the uric acid output is too high, allopurinol should be the treatment of first choice. Increased fluid intake is recommended; maintenance treatment with colchicine is not advised. Consultation with or referral to a rheumatologist is indicated in the case of doubt about the diagnosis of 'acute gout' or 'complicated gout', or (suspected) bacterial arthritis and insufficient treatment effect.

Topics: Acute Disease; Adrenal Cortex Hormones; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Benzbromarone; Chronic Disease; Colchicine; Gout; Gout Suppressants; Humans; Netherlands; Practice Guidelines as Topic; Recurrence; Uricosuric Agents

Although oxygen-derived free radicals are known to play a role in cell injury and DNA alterations, the role of active oxidants in chronic pancreatitis has not been fully elucidated. Using WBN/Kob rats, which spontaneously develop chronic pancreatitis-like lesions, we investigated whether xanthine oxidase (XOD)-derived oxygen radicals are involved in pancreatic tissue injury.. WBN/Kob rats were fed a control or a tungsten diet. The latter depletes XOD activity. Histologic al changes, glutathione (GSH) content and XOD and superoxide dismutase (SOD) activities were determined in pancreatic tissue. Pancreatic 8-hydroxy-deoxyguanosine (8-OH-dG) levels and lithostathine mRNA were also examined.. In WBN/Kob rats, parenchymal destruction and fibrosis developed at approximately 12 weeks of age and progressed with each month. The activity of XOD was significantly higher in the early period (8-12 weeks), whereas the levels of GSH and SOD decreased after 16 weeks. Levels of 8-OH-dG in WBN/Kob rats were significantly elevated at 16 weeks. Lithostathine mRNA levels started to increase at 8 weeks, but were suppressed at 16 weeks. The tungsten diet significantly attenuated the histological changes in WBN/Kob rats. The increase in pancreatic XOD activity and 8-OH-dG content in WBN/Kob rats was significantly inhibited by the tungsten diet and lithostathine mRNA levels remained high at 16 weeks.. These results suggest that oxygen radicals generated by XOD play an important role in oxidative DNA damage and the development of chronic pancreatic injury.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amylases; Animals; Body Weight; Calcium-Binding Proteins; Chronic Disease; Deoxyguanosine; Glutathione; Lithostathine; Nerve Tissue Proteins; Pancreas; Pancreatitis; Procollagen-Proline Dioxygenase; Rats; Rats, Inbred Strains; Reactive Oxygen Species; RNA, Messenger; Superoxide Dismutase; Xanthine Oxidase

Topics: Allopurinol; Cardiology; Chronic Disease; Clinical Trials as Topic; Endothelium, Vascular; Enzyme Inhibitors; Heart Failure; Humans; Models, Cardiovascular; Nitric Oxide; Oxidative Stress; Vasodilation; Xanthine Oxidase

The exact mechanisms of the development of pancreatic fibrosis are still unknown. To clarify the relationship between pancreatic fibrosis and free radicals, the effect of the administration of a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DDC), on pancreatic fibrosis in rats was studied. A single intraperitoneal injection of 500 mg/kg of DDC significantly reduced SOD activity and significantly increased lipid peroxidation products in the pancreas, showing no histologic changes of inflammation or necrosis. Repeated administration of 500 mg/kg DDC, twice a week, caused inter- and intralobular fibrosis with atrophy of acinar cells in the pancreas for at least 2 weeks without fibrosis of the liver and kidney. Administration of allopurinol showed preventive effects against DDC-induced pancreatic fibrosis. In conclusion, repeated administration of DDC, which caused pancreatic fibrosis, is a new experimental model of pancreatic fibrosis from the viewpoint of oxidative stress.

Topics: Allopurinol; Animals; Atrophy; Chronic Disease; Ditiocarb; Enzyme Inhibitors; Fibrosis; Free Radicals; Injections, Intraperitoneal; Lipid Peroxidation; Lipid Peroxides; Male; Oxidative Stress; Pancreas; Pancreatitis; Rats; Rats, Wistar; Superoxide Dismutase

Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling. Because hypoxia might promote generation of oxidative stress in vivo, we hypothesized that oxidative stress may play a role in the hypoxia-induced cardiopulmonary changes and examined the effect of treatment with the antioxidant N-acetylcysteine (NAC) in rats. NAC reduced hypoxia-induced cardiopulmonary alterations at 3 wk of hypoxia. Lung phosphatidylcholine hydroperoxide (PCOOH) increased at days 1 and 7 of the hypoxic exposure, and NAC attenuated the increase in lung PCOOH. Lung xanthine oxidase (XO) activity was elevated from day 1 through day 21, especially during the initial 3 days of the hypoxic exposure. The XO inhibitor allopurinol significantly inhibited the hypoxia-induced increase in lung PCOOH and pulmonary hypertension, and allopurinol treatment only for the initial 3 days also reduced the hypoxia-induced right ventricular hypertrophy and pulmonary vascular thickening. These results suggest that oxidative stress produced by activated XO in the induction phase of hypoxic exposure contributes to the development of chronic hypoxic pulmonary hypertension.

Topics: Acetylcysteine; Allopurinol; Animals; Antioxidants; Chronic Disease; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Male; Oxidative Stress; Oxygen; Phosphatidylcholines; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Tunica Media; Ventricular Function, Right; Xanthine Oxidase

High concentrations of serum xanthine oxidase (XO) have been reported during human liver disease and hepatocyte injury in experimental settings. However, it is unclear whether this elevation reflects hepatocyte necrosis or has a different meaning.. The serum level of XO in 64 patients with chronic liver disease (17 patients with cirrhosis, 30 with chronic hepatitis, and 17 with cholestatic disorders) and in 12 control subjects was determined by a competitive ELISA. Conventional serum markers of liver damage were assessed in all patients, and grading and staging were scored in the chronic hepatitis group according to Knodell.. The XO serum levels were significantly higher in the patients than in the controls. The differences were also significant when controls were compared to patients with chronic hepatitis and cholestatic disorders separately, but not when compared to the cirrhosis group. Patients with cholestatic disorders had XO values higher than those of patients with cirrhosis or chronic hepatitis. XO levels did not correlate with stage and grade in chronic hepatitis group. We found a weak but significant positive correlation in patients between XO serum level and gamma-glutamyl transpeptidase (r = 0.37). This correlation was stronger when chronic hepatitis (r = 0.42) and, especially cholestatic disorders (r = 0.71), were separately tested, but was absent in the cirrhosis group. The XO values positively correlated with alkaline phosphatase in patients with cholestatic disorders. A level of serum XO >32 microg/ml specifically identified cholestatic disorders in our study population.. A marked elevation of serum XO in patients with chronic liver disease seems to reflect the presence of cholestasis. No correlation between XO levels and histological or serum evidence of hepatocyte necrosis was found in these patients.

Topics: Adult; Cholestasis; Chronic Disease; Female; Hepatitis, Viral, Human; Humans; Liver Cirrhosis; Male; Middle Aged; Xanthine Oxidase

Using a reversible chronic constriction injury (CCI) model of neuropathic pain, we previously demonstrated that changes in thermal hyperalgesia correlate with the changes in peripheral microvascular blood flow in the affected paw, and that recovery can be assessed by normalization of both behavioral and vascular responses. Using the same model, this study examined age-related changes in recovery after nerve injury and the involvement of free radicals and nitric oxide (NO) in these changes. Four loose, nonconstrictive ligatures were applied to the sciatic nerve in the right, mid-thigh region of young and old (3 and 24 months) Sprague Dawley rats. All rats were monitored weekly (for 8-10 weeks) for their thermal threshold using a 46 degrees C water bath and some groups were used to examine endothelial and smooth muscle-dependent microvascular responses to substance P (SP) and sodium nitroprusside (SNP), respectively. These substances were perfused over the base of blisters raised on the footpad innervated by the injured nerve. Free radical activity in the sciatic nerve was assessed by measuring the activity of xanthine oxidase (XO) and lipid hydroperoxides (LPO). Young rats showed signs of recovery (reduction in thermal hyperalgesia and improvement of peripheral microvascular blood flow) from the fifth week. No signs of recovery were observed in old rats for 8 weeks, with some reduction in thermal hyperalgesia observed by weeks 9 and 10. XO activity was significantly higher in young injured nerves compared to sham (400%) and was even significantly greater in old injured nerves (680%). Similarly, old injured nerves showed 300% increase in LPO levels compared to sham. The role of reactive oxygen species (ROS) in delayed recovery in old rats was examined using the antioxidant tirilazad mesylate. Tirilazad (20 mg/kg) was injected intramuscularly (im) in the mid-thigh region starting on day 1 post CCI, (early treatment) or day 7 (late treatment). Levels of LPO in the injured sciatic nerves were significantly reduced using either early or late treatment, however tirilazad had opposing effects on recovery, prolonging or alleviating thermal hyperalgesia, respectively. The role of neuronal nitric oxide (nNO) was then examined using the specific neuronal nitric oxide synthase (nNOS) inhibitor, 3-bromo-7-nitroindazole (3Br-7NI) (10 mg/kg). 3Br-7NI resulted in a significant alleviation of thermal hyperalgesia with improvement in the vascular responses from weeks 5 and

Topics: Aging; Animals; Antioxidants; Chronic Disease; Constriction, Pathologic; Free Radicals; Hot Temperature; Hyperalgesia; Lipid Peroxides; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pain; Pregnatrienes; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sciatic Nerve; Xanthine Oxidase

Activities of hepatic xanthine oxidase (XO) and xanthine dehydrogenase (XD), serum liver enzymes, and reduced glutathione (GSH) were determined in livers of chronic cholestatic rats. The common bile duct was ligated (CBDL) and rats were randomized to either an untreated group or to treatment with allopurinol, a competitive XO inhibitor, or received a tungsten-supplemented diet to inactivate XO and XD, or received antioxidants vitamin C and vitamin E. One group underwent only sham laparotomy. After 4 weeks, in untreated CBDL animals serum aspartate aminotransferase and bilirubin concentrations were significantly elevated and hepatic GSH was significantly decreased when compared with the sham-operated group. Histochemical and enzymatic determinations of XD and XO showed a significant increase in hepatic XO activity after CBDL. Treatment with allopurinol and a tungsten-supplemented, molybdenum-free diet significantly attenuated serum liver enzymes, hepatic XO activity, and improved hepatic GSH levels, whereas vitamins C and E had a positive effect only on hepatic GSH levels. Our results support the hypothesis that cholestasis-induced hepatocellular injury is partially triggered by oxidative processes derived from increased hepatic XO activity. Inhibition and inactivation of XO exerts a hepatocellular protective effect in chronic cholestasis.

Topics: Allopurinol; Animals; Cholestasis; Chronic Disease; Enzyme Inhibitors; Glutathione; Liver; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Tungsten; Xanthine Dehydrogenase; Xanthine Oxidase

Results of study into the condition of reduction-oxidation processes, in particular of those associated with generation of the superoxide radical, are submitted together with those of determination of levels of inorganic phosphate which is known to be an important indicator of the tissue bioenergy potential, in 112 patients presenting with a recurring form of nephrolithiasis exposed to a multiple-modality treatment that included conventional antiinflammatory and antibacterial therapy plus "open" and endourological operations on kidneys and ureters. The multiple-modality treatment of the main group patients was supplemented with phlogenzyme, a drug of II generation systemic enzymotherapy. An enhanced generation of superoxide radical was recordable having developed in the wake of a steady increase in the activity of xanthinoxidase. The authors have come to the conclusion that the conducted therapeutic intervention, especially as part of systemic enzyme therapy, results in decline of activity of the xanthine oxidation processes and brings about a change in the blood:urine inorganic phosphate concentrations ratio.

Topics: Chronic Disease; Combined Modality Therapy; Enzyme Therapy; Humans; Kidney Calculi; Oxidation-Reduction; Phosphates; Pyelonephritis; Recurrence; Superoxides; Urodynamics; Urologic Surgical Procedures; Xanthine Oxidase

Topics: Administration, Oral; Aged; Allopurinol; Chronic Disease; Desensitization, Immunologic; Drug Hypersensitivity; Female; Gout; Gout Suppressants; Heart Diseases; Humans; Kidney Failure, Chronic; Urea

Not all gout presents with involvement of the big toe, and not all gout patients are middle-aged men. Chronic gout may mimic rheumatoid arthritis; hyperuricemia may develop in postmenopausal women and in organ transplant recipients who are being treated with immunosuppressive agents. Both classic and nonclassic cases may benefit from new therapeutic agents.

Topics: Aged; Algorithms; Allopurinol; Chronic Disease; Diagnosis, Differential; Female; Gout; Gout Suppressants; Humans; Hypertension; Losartan; Male; Middle Aged; Oxypurinol; Urate Oxidase; Virus Diseases

Chagas disease is endemic in Chile. Allopurinol and itraconazole have activity against Trypanosoma cruzi and are recommended for the treatment of chronic disease in adults.. To evaluate the chemotherapeutic effects of allopurinol and itraconazole using conventional and non conventional serologic tests.. Sera of 90 patients with chronic Chagas disease were studied before and after 9 to 11 months of treatment with allopurinol or itraconazole and after two months of treatment with placebo. Indirect immunofluorescence, ELISA and Western Blot analysis were the conventional serologic tests used and antibody dependent complement mediated lysis (CoML) the non conventional test.. There were no differences in ELISA and indirect immunofluorescence tests before and after therapy. Antigenic recognition profiles by Western Blot showed qualitative and quantitative differences in a small number of cases. CoML showed that the greater negativity was achieved in the Chagasic group treated with allopurinol or itraconazole that had a negative xenodiagnosis before drug treatment (35.8 and 61.6%, respectively).. There is a reversion of lytic activity in sera of patients with negative xenodiagnosis before treatment, suggesting the parasitemia could be an important parameter to be considered in the chemotherapy of Chagas disease.

Topics: Adolescent; Adult; Allopurinol; Antiprotozoal Agents; Chagas Disease; Child; Chronic Disease; Follow-Up Studies; Humans; Itraconazole; Middle Aged

We present an unusual complication of chronic tophaceous gout in a 63-year-old man with a 27-year history of gout, who could not be treated with allopurinol due to previous allopurinol-induced neutropenia. The patient presented with a progressively enlarging, painful mass on the bottom of his right foot, which caused difficulty wearing shoes and walking. Extirpation of the tophus and first metatarsophalangeal joint arthroplasty were successfully employed for management of this condition.

Topics: Allopurinol; Chronic Disease; Diagnosis, Differential; Disease Progression; Foot Diseases; Gout; Gout Suppressants; Humans; Male; Middle Aged; Radiography

Imbalances between oxidant formation and antioxidative defense are associated with the pathogenesis of several chronic inflammatory disorders of the respiratory tract. Therefore, a role of oxidative stress in chronic upper airway tract infections can be anticipated.. To determine if patients with chronic sinusitis demonstrate a reduced antioxidative tissue status.. The levels of 3 biologically important antioxidants, reduced glutathione and oxidized glutathione, uric acid, and vitamin E, were determined biochemically in mucosal biopsy specimens from the uncinate process of patients with chronic sinusitis and healthy controls.. Inflamed mucosa samples were obtained from 9 patients with chronic sinusitis during functional endoscopic sinus surgery. Normal mucosa samples were collected from 10 healthy controls during surgery for nasal obstruction.. The data (presented as mean +/- SD) show a significant reduction (P < or = .05) of reduced glutathione levels (0.3 +/- 0.1 mumol/g wet weight) and uric acid levels (2.7 +/- 0.4 mumol/g wet weight) in mucosa samples obtained from patients with chronic sinusitis compared with healthy controls (0.6 +/- 0.2 and 3.4 +/- 0.6 mumol/g wet weight, respectively). No difference was found in oxidized glutathione (24 +/- 8 vs 25 +/- 15 nmol/g wet weight) and vitamin E (20.5 +/- 7.9 vs 22.5 +/- 6.9 nmol/g wet weight) levels between both groups.. Decreased levels of both reduced glutathione and uric acid in patients with chronic sinusitis lead to a diminished antioxidant defense, which may be associated with the pathogenesis of upper respiratory tract disorders. The vitamin E level seems less important. This finding may offer perspectives for pharmacotherapeutic intervention with antioxidants.

Topics: Case-Control Studies; Chronic Disease; Female; Glutathione; Humans; Male; Middle Aged; Nasal Mucosa; Oxidative Stress; Sinusitis; Uric Acid; Vitamin E; Xanthine Oxidase

Two patients with chronic sialoadenitis had features of Bartter's and Gitelman's syndrome, respectively. The main complaints were leg paraesthesiae and acute arthritis. A good response to oral K+ supplementation, allopurinol and low-dose prednisone was obtained. The features of Sjögren's-related renal diseases are reviewed.

Topics: Adult; Aged; Alkalosis; Allopurinol; Anti-Inflammatory Agents; Antimetabolites; Bartter Syndrome; Calcium; Chronic Disease; Dose-Response Relationship, Drug; Female; Humans; Hypokalemia; Magnesium; Potassium; Prednisone; Sialadenitis; Sjogren's Syndrome; Syndrome

Topics: Allopurinol; Chronic Disease; Drug Evaluation; Humans; Male; Prostatitis

Spontaneous bacterial infections and septicaemia result in morbidity and mortality in patients with portal hypertension and obstructive jaundice.. The aim of this study in rats was to investigate the incidence of bacterial translocation in portal hypertension and obstructive jaundice, and to evaluate the effects of allopurinol and glutamine.. Rats were subjected to sham laparotomy (SL), portal hypertension (PH) by calibrated stenosis of the portal vein, and common bile duct ligation (CBDL). Animals of each group were either treated with allopurinol (50 mg/kg twice a week), glutamine (1 g/kg/d), and allopurinol and glutamine.. After four weeks, significant bacterial translocation in the untreated PH and CBDL rats occurred. Intestinal mucosal malondialdehyde concentrations (MDA), as an indicator for lipid peroxidation, and myeloperoxidase activity (MPO) released from activated neutrophils were also significantly increased (p < 0.01). Allopurinol and glutamine in PH and CBDL rats improved bacterial translocation, and decreased MDA and MPO values (p < 0.01).. In PH and CBDL rats significant bacterial translocation, ileal mucosal lipid peroxidation, and neutrophil derived MPO activity occurred. Allopurinol and glutamine significantly reduced bacterial translocation, as well as ileal mucosal MDA and MPO activities.

Topics: Allopurinol; Analysis of Variance; Animals; Bacterial Translocation; Cholestasis, Extrahepatic; Chronic Disease; Common Bile Duct; Enzyme Inhibitors; Glutamine; Hypertension, Portal; Ileum; Laparotomy; Ligation; Male; Malondialdehyde; Peroxidase; Random Allocation; Rats; Rats, Sprague-Dawley

In their ten years renal biopsy material authors found nine cases of chronic glomerulonephritides with predominantly IgM deposition in the mesangium which reach the diagnosis of IgM nephropathy. This paper on the basis of a typical case deal with the immunopathology, diagnosis, prognosis and therapy of the disease.

Topics: Adult; Allopurinol; Angiotensin-Converting Enzyme Inhibitors; Antimetabolites; Ascorbic Acid; Biopsy; Child; Chronic Disease; Drug Combinations; Drug Therapy, Combination; Glomerulonephritis, Membranoproliferative; Glucocorticoids; Humans; Immunoglobulin M; Male; Methylprednisolone; Prognosis; Radioisotope Renography; Rutin

The effect of Allopurinol (ALLO), on adjuvant arthritis was studied in rats and compared with the effect of indomethacin (IND). Drugs were given by intraperitoneal injection for each day beginning from the day of adjuvant injection (day 0) and continued until the 16th day. Paw swelling was measured on days 4, 17 and 29, and secondary lesions were assessed on days 17 and 29. Polymorphonuclear leukocyte (PMNs) count was also evaluated on day 17. ALLO, at relatively high doses (25-50 mg/kg), reduced paw swelling of the adjuvant-injected extremity on day 4; lower doses (6.25-12.5 mg/kg), however, elicited the same inhibitory effect on day 17. IND (0.25 mg/kg) also prevented paw swelling on days 4 and 17. Both ALLO and IND reduced the secondary lesions on days 17 and 29 and prevented the increase in polymorphonuclear leukocytes during the development of adjuvant arthritis. Possible mechanisms of the antiinflammatory effect of ALLO in adjuvant arthritis are discussed.

Topics: Allopurinol; Animals; Arthritis, Experimental; Chronic Disease; Female; Foot; Freund's Adjuvant; Indomethacin; Injections, Intraperitoneal; Leukocyte Count; Male; Neutrophils; Rats

To determine the efficacy and safety of slow oral desensitization in the management of allopurinol-related pruritic cutaneous eruptions.. Nine patients with renal insufficiency and chronic tophaceous gouty arthritis, who had to interrupt their allopurinol therapy because of an allergic-type pruritic maculopapular eruption, were enrolled in an allopurinol oral desensitization protocol using a schedule of gradually increasing doses.. Cautious reinstitution of allopurinol was successfully accomplished in all nine patients, but four individuals required dose adjustment because of development of a mild, recurrent, macular rash early during the protocol at allopurinol doses of less than or equal to 5 mg/d. Transient, postdesensitization cutaneous reactions occurred in two patients, one of whom also had an early rash.. Oral desensitization to the minor rashes induced by allopurinol is a feasible and acceptably safe approach to therapy, particularly for those with renal insufficiency in whom no substitute urate-lowering drug is available.

Topics: Administration, Oral; Adolescent; Adult; Aged; Allopurinol; Chronic Disease; Desensitization, Immunologic; Drug Eruptions; Female; Gout; Humans; Kidney Failure, Chronic; Male; Middle Aged; Pruritus

Topics: Allopurinol; Chronic Disease; Gout; Humans; Male; Middle Aged; Panniculitis; Recurrence

Transient mucosal ischemia may cause oxygen-derived free radical production by xanthine oxidase, precipitating pouchitis after ileal pouch-anal anastomosis. Our aim, therefore, was to determine the effect of allopurinol, a xanthine oxidase inhibitor, in patients with acute and chronic pouchitis. Acute pouchitis was characterized clinically by sporadic episodes of increased frequency and decreased viscosity of stools, hematochezia, fever, malaise, and pelvic pain, which resolved promptly with treatment. Chronic pouchitis patients required continuous treatment to remain asymptomatic and invariably developed the signs and symptoms of pouchitis within one week following cessation of therapy. Eight patients with acute pouchitis were treated with allopurinol (300 mg p.o. b.i.d.) during the episode. Fourteen patients with chronic pouchitis had their standard antibiotic therapy discontinued while still asymptomatic; they were then given allopurinol (300 mg p.o. b.i.d.) for 28 days. Acute pouchitis resolved promptly in four of eight patients. Seven of the 14 patients with chronic pouchitis responded completely with no recurrence of symptoms during treatment. Allopurinol either terminated an episode of acute pouchitis or prevented pouchitis from recurring in 50 percent of patients. These data support a role for mucosal ischemia and oxygen free radical production in the etiology of pouchitis.

Topics: Acute Disease; Adult; Allopurinol; Chronic Disease; Female; Free Radicals; Humans; Ileal Diseases; Inflammation; Intestinal Mucosa; Male; Middle Aged; Oxygen; Proctocolectomy, Restorative; Xanthine Oxidase

The sensitivity of fibroblasts derived from patients with chronic actinic dermatitis (CAD) ultraviolet B (UVB), UVA and superoxide radical was examined. Fibroblasts from the skin of 3 patients with CAD showed abnormal hypersensitivity after exposure to mid-UV (UVB) and near-UV (UVA) radiation in both the dividing and quiescent phases. In their dividing phases, the 3 cell strains (CAD1TO, CAD2TO and CAD3TO) exhibited 78, 55 and 82 J/m2 for the mean lethal dose (Do) values in UVB survival curves. In the quiescent phases their Do values were 262, 226 and 165 J/m2, respectively. Regarding UVA sensitivity, Do value in the dividing phases were 4.9, 3.9 and 3.8 x 10(4) J/m2, and in the quiescent phases, 2.0, 1.9 and 1.7 x 10(5) J/m2. Do values were lower than in the cell strains derived from healthy individuals (Do = 120 +/- 18 and 390 +/- 72 J/m2) for UVB sensitivity in the dividing and quiescent phases and (5.9 +/- 0.6) x 10(4) and (3.2 +/- 1.0) x 10(5) J/m2 for UVA sensitivity in the dividing and quiescent phases. DNA repair synthesis was similar between the cell lines. Furthermore, the 3 CAD cell lines showed a higher sensitivity to superoxide radical generated by hypoxanthine/xanthine oxidase treatment. These results suggest that patients with CAD may suffer from a defect in dealing with damage induced by oxygen radicals.

Topics: Cell Line; Cell Survival; Chronic Disease; Fibroblasts; Free Radicals; Humans; Hypoxanthine; Hypoxanthines; Male; Middle Aged; Photosensitivity Disorders; Skin; Superoxides; Ultraviolet Rays; Xanthine Oxidase

Refractory peptic ulceration refers to those gastric and duodenal ulcers that are slow to heal despite active treatment. Oxygen-derived free radicals are cytotoxic and promote tissue injury. This report shows that radical scavengers stimulate the healing of refractory peptic ulceration, thus, providing a valuable method for the treatment of such ulceration.

Topics: Adult; Allopurinol; Chronic Disease; Cimetidine; Dimethyl Sulfoxide; Duodenal Ulcer; Female; Free Radical Scavengers; Free Radicals; Humans; Hydroxides; Hydroxyl Radical; Male; Middle Aged; Stomach Ulcer

Sensitivity to allopurinol, which occurs in 10-15% of patients, can seriously limit the drug's use in chronic tophaceous gout. Oral allopurinol desensitization has been advocated for sensitive patients in whom use of the drug is warranted. We report the successful use of intravenous allopurinol desensitization in a patient with chronic tophaceous gout in whom oral desensitization had previously failed.

Topics: Administration, Oral; Allopurinol; Chronic Disease; Desensitization, Immunologic; Drug Hypersensitivity; Gout; Humans; Injections, Intravenous; Male; Middle Aged

Oxygen-derived free radicals are cytotoxic and mediate tissue damage. Allopurinol prevents the formation of superoxide radicals and dimethyl sulphoxide (DMSO) scavenges the hydroxyl ones. Intraperitoneal reserpine (5 mg/kg every day for 5 days) produced chronic gastric ulceration in all rats after 4 weeks. Animals gavaged with 1 ml/day of each of 1% allopurinol and 1% DMSO for 4 weeks developed ulceration in 60% of cases; however this ulceration developed in only 20% of animals similarly gavaged with 2% solutions. Rats gavaged with 1 ml/day of each of 5% allopurinol and 5% DMSO for 4 weeks were completely protected against the reserpine-induced chronic gastric ulceration. This protection was not associated with any significant effect on the H+ output of the rat stomach. The results suggest that in the rat, oxygen-derived free radicals are responsible for the development of chronic gastric ulceration and that removing these radicals protects against the said ulceration without influencing acid secretion, i.e. cytoprotection.

Topics: Allopurinol; Animals; Chronic Disease; Dimethyl Sulfoxide; Female; Free Radicals; Gastric Acid; Hydroxides; Hydroxyl Radical; Male; Rats; Rats, Inbred Strains; Reserpine; Stomach Ulcer; Superoxides

Topics: Aged; Allopurinol; Chronic Disease; Drug Hypersensitivity; Female; Gout; Humans; Oxypurinol; Prognosis

In an attempt to define why the joint synovial cavity is prone to develop persistent synovial inflammation we show that hypoxia is induced by pressure changes caused by exercise in the presence of an inflammatory effusion. On resting 'reperfusion injury' may take place. The biochemistry of reperfusion injury has only recently been defined and perhaps surprisingly for an insult that has hypoxia as its central ingredient involves the subsequent production of oxygen derived free radical species. We apply the reaction sequences that are believed to occur during hypoxic/reperfusion injury to the joint synovial cavity and, on the basis of reported 'in vivo' observations, suggest novel therapeutic approaches that we believe are applicable to the treatment of persistent synovial inflammation.

Topics: Animals; Cats; Chronic Disease; Free Radicals; Humans; Hypoxia; Ischemia; Knee Joint; Oxygen; Partial Pressure; Perfusion; Physical Exertion; Rats; Synovitis; Xanthine Oxidase; Xanthines

Topics: Adult; Allopurinol; Chronic Disease; Drug Evaluation; Drug Therapy, Combination; Female; Gout; Humans; Male; Middle Aged; Probenecid; Sulfinpyrazone; Time Factors; Uric Acid

A case of chronic veno-occlusive disease of the liver manifested by ascites in a 59-year-old Japanese male is described. The patient had not been exposed to pyrrolizidine alkaloids, but had been receiving allopurinol for hyperuricemia, the only drug taken throughout the period in which the hepatic lesion developed. The hepatic veins and inferior vena cava were patent according to angiography. The first biopsy showed histological characteristics of the disease and the following two biopsies demonstrated the progression of the hepatic lesion from central fibrosis to non-portal cirrhosis. Morphometric analysis of the sublobular and central veins in the three serial biopsy specimens demonstrated stepwise decrease of the ratio of the veins per portal triad and stepwise increase of severely obliterative veins.

Topics: Allopurinol; Budd-Chiari Syndrome; Chronic Disease; Humans; Liver; Male; Middle Aged; Uric Acid

Topics: Acute Disease; Allopurinol; Anti-Inflammatory Agents; Arthritis; Chronic Disease; Colchicine; Gout; Humans; Kidney Diseases; Uric Acid; Uricosuric Agents

Telescoped digits of the hands and feet developed in a 69-year-old male with severe chronic tophaceous gout during allopurinol treatment. Extensive osseous tophi, resorbed rapidly during therapy with this xanthine oxidase inhibitor and not replaced by new bone matrix, were responsible for the deformity. Several hypotheses are advanced to explain the failure of bone erosions to heal.

Topics: Aged; Allopurinol; Chronic Disease; Foot Deformities, Acquired; Gout; Hand Deformities, Acquired; Humans; Male

Serum xanthine oxidase activity was measured by a radiochemical method in 137 consecutive patients with jaundice of varying etiology and in 40 non-jaundiced patients with liver or other disease. Serum xanthine oxidase was markedly increased, up to 50 times the upper normal limit (mean + 2 S.D.), in 32 out of 34 patients with infectious hepatitis. A slight elevation of serum xanthine oxidase, up to twice the upper normal limit, was found in 2 out of 49 patients with extrahepatic obstructive jaundice and in 4 out of 20 patients with chronic renal failure. In comparison to serum glutamic-oxaloacetic transaminase and lactate dehydrogenase serum xanthine oxidase appeared to be the more sensitive and specific indicator of acute hepatocellular damage.

Topics: Aspartate Aminotransferases; Chronic Disease; Hepatitis A; Humans; Jaundice; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Liver Cirrhosis; Liver Neoplasms; Myocardial Infarction; Neoplasm Metastasis; Xanthine Oxidase

Topics: Allopurinol; Amenorrhea; Busulfan; Chlorambucil; Chronic Disease; Drug Eruptions; Female; Hemolysis; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukocytosis; Lymphocytosis; Prednisolone; Pulmonary Fibrosis; Splenectomy; Vincristine

Topics: Arginase; Biopsy; Child; Child, Preschool; Chronic Disease; Female; Hepatitis; Humans; Infant; Infant, Newborn; Infections; Liver; Liver Cirrhosis; Liver Diseases; Male; Nephrotic Syndrome; Nutrition Disorders; Xanthine Oxidase

Topics: Allopurinol; Animals; Chronic Disease; Cystitis; Dog Diseases; Dogs

Topics: Absorption; Adult; Allopurinol; Biological Transport; Chronic Disease; Glomerular Filtration Rate; Humans; Inulin; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Tubules; Middle Aged; Pyrazinamide; Uremia; Uric Acid; Uricosuric Agents

Topics: Adrenocorticotropic Hormone; Allopurinol; Chronic Disease; Colchicine; Dexamethasone; Diet Therapy; Gout; Humans; Indomethacin; Lidocaine; Phenylbutazone; Prednisolone; Probenecid; Recurrence; Synovial Fluid; Uric Acid

Topics: Allopurinol; Chronic Disease; Drug Combinations; Gout; Humans; Indomethacin; Oxyphenbutazone; Phenylbutazone; Uricosuric Agents

Topics: Adenine Nucleotides; Allopurinol; Aminohydrolases; Blood Cell Count; Blood Coagulation Disorders; Blood Platelets; Carbon Isotopes; Chronic Disease; Hemoglobins; Humans; Leukemia, Myeloid; Nucleosides; Uric Acid

Topics: Allopurinol; Chronic Disease; Colchicine; Gout; Humans; Joints; Kidney; Probenecid; Sulfinpyrazone; Uric Acid

Topics: Acute Disease; Adult; Allopurinol; Anti-Inflammatory Agents; Chronic Disease; Diagnosis, Differential; Diet Therapy; Female; Gout; Humans; Male; Middle Aged; Purines; Uric Acid; Uricosuric Agents

Topics: Acute Disease; Allopurinol; Chronic Disease; Colchicine; Gout; Humans; Indomethacin; Metabolic Diseases; Phenylbutazone; Salicylates; Uric Acid; Uricosuric Agents

Topics: Acute Disease; Allopurinol; Chronic Disease; Colchicine; Diabetes Complications; Gout; Humans; Hypertension; Indomethacin; Purines; Pyrazoles; Uricosuric Agents

Topics: Allopurinol; Chronic Disease; Colchicine; Colorimetry; Female; Gout; Humans; Male; Purines; Sulfinpyrazone; Uric Acid; Xanthine Oxidase

Topics: Acute Disease; Allopurinol; Anti-Inflammatory Agents; Chronic Disease; Gout; Humans; Oxyphenbutazone; Phenylbutazone; Sulfinpyrazone; Uricosuric Agents

Topics: Adult; Aged; Allopurinol; Anemia; Arthritis; Bicarbonates; Blood Sedimentation; Chronic Disease; Female; Gout; Humans; Joint Diseases; Male; Middle Aged; Phenylbutazone; Physical Exertion; Probenecid; Uric Acid