oxypurinol and Heart-Failure

Several trials have been completed in patients with heart failure (HF) treated with uric acid (UA)-lowering agents with inconsistent results. We aimed to investigate whether lowering UA would have an effect on mortality and cardiovascular (CV) events in patients with HF in a systematic review and meta-analysis. The primary outcome measures were all-cause mortality, CV mortality, CV events, and CV hospitalization in patients with HF. We included 11 studies in our final analysis. Overall, allopurinol treatment was associated with a significant increase in the risk for all-cause mortality (hazard ratio [HR]: 1.24, 95% confidence interval [CI]: 1.04-1.49, P = .02). The trial heterogeneity is high (heterogeneity χ

Topics: Allopurinol; Enzyme Inhibitors; Febuxostat; Heart Failure; Humans; Oxypurinol; Uric Acid; Xanthine Oxidase

Oxipurinol [alloxanthine, Oxyprim, oxypurinol] is the active metabolite of the only commercially available xanthine oxidase inhibitor, allopurinol. Oxipurinol is also a xanthine oxidase inhibitor. Oxipurinol is currently being developed by Cardiome Pharma. It is waiting for approval in the US for the treatment of allopurinol-intolerant hyperuricaemia (gout) and is in phase III trials for the treatment of congestive heart failure. Allopurinol is indicated for the treatment of symptomatic hyperuricaemia, or gout. Approximately 3-5% of patients receiving allopurinol develop intolerance to the drug. Oxipurinol was originally developed by Burroughs Wellcome (later GlaxoSmithKline), and has been available on a compassionate-use basis since 1967 for use in allopurinol-intolerant patients. The licensee company ILEX Oncology has stated that oxipurinol does not have patent protection. Oxipurinol's potential for treatment of congestive heart failure is based on the possibility that xanthine oxidase inhibitors may improve myocardial work efficiency by sensitising cardiac muscle cells to calcium ions, which are a key determinant of cardiac muscle function. This results in more efficient contraction of cardiac muscle cells, without the same increase in oxygen demand. At the second annual BioPartnering North America conference (BPN-2004) [February 2004, Vancouver, Canada], Cardiome Pharma stated that it was seeking a commercialisation partner to market and distribute oxipurinol in the US for the treatment of allopurinol-intolerant hyperuricaemia. In 1995, ILEX Oncology obtained an exclusive licence to oxipurinol from Burroughs Wellcome. Burroughs Wellcome later became part of Glaxo Wellcome, which merged with SmithKline Beecham in December 2000 to form GlaxoSmithKline. ILEX's licence agreement is now with GlaxoSmithKline and The Wellcome Foundation. In December 2001, ILEX granted Paralex, a privately held New York-based company, an exclusive sublicence to all of ILEX's rights to oxipurinol for the treatment of hyperuricaemia in allopurinol-intolerant patients. Paralex additionally gained the right to develop and commercialise oxipurinol in all fields, under data and technology owned by ILEX. Furthermore, Paralex had licensed certain intellectual property rights from The John Hopkins University relating to cardiovascular applications of xanthine oxidase inhibitors. Paralex was acquired by Cardiome Pharma in March 2002. Cardiome Pharma announced early in May 2002 that it

Topics: Drugs, Investigational; Enzyme Inhibitors; Heart Failure; Humans; Oxypurinol

This study evaluated whether a xanthine oxidase (XO) inhibitor, oxypurinol, produces clinical benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy.. Increased XO activity may contribute to heart failure pathophysiology.. Patients (n = 405) were randomized to oxypurinol (600 mg/day) or placebo. Efficacy at 24 weeks was assessed using a composite end point comprising heart failure morbidity, mortality, and quality of life.. The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving oxypurinol or placebo. Oxypurinol reduced serum uric acid (SUA) by approximately 2 mg/dl (p < 0.001). In a subgroup analysis, patients with elevated SUA (>9.5 mg/dl, n = 108) responded favorably to oxypurinol (p = 0.02 for interaction term), whereas oxypurinol patients with SUA <9.5 mg/dl exhibited a trend towards worsening. In addition, SUA reduction to oxypurinol correlated with favorable clinical response. Within the entire oxypurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who worsened (-2.3 +/- 2.1 mg/dl vs. -1.0 +/- 1.9 mg/dl, p = 0.0006). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome.. Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Serum uric acid may serve as a valuable biomarker to target XO inhibition in heart failure. (Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure; NCT00063687).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Double-Blind Method; Enzyme Inhibitors; Female; Health Status Indicators; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Oxypurinol; Quality of Life; Surveys and Questionnaires; Systole; Uric Acid; Xanthine Oxidase

Reactive oxygen species (ROS) have been linked to hypertrophy, remodeling and abnormal excitation-contraction coupling. Previous data demonstrated that an increase in oxidative stress is associated to the pathogenesis of congestive heart failure (CHF). We examined whether inhibition of the superoxide anion (*O2(-))-generating enzyme xanthine oxidase (XO) with oxypurinol may improve cardiac function in patients with CHF.. A randomized, placebo-controlled, double-blind study on 60 patients (30/group) with New York Heart Association class II-III CHF, comparing 600-mg/day oxypurinol during 1 month with placebo, added to standard therapy. Effects on left ventricular ejection fraction (LVEF), serum uric acid (SUA) level, and 6-minute walking test were analyzed. SUA decreased by 16.0 +/- 2.8 mg/L from baseline to Week 4 in the oxypurinol group relative to placebo (P < .01, n = 30 per group). LVEF showed an increase of 4.7 +/- 2.6% from baseline to Week 4 in the oxypurinol group relative to placebo that did not reach statistical significance (P < .08). When patients with LVEF > 40% at baseline were excluded, a statistically significant increase of 6.8 +/- 2.8% from baseline to Week 4 was seen in the oxypurinol group relative to placebo (P < .02, n = 26 placebo, n = 21 oxypurinol). No treatment-related adverse effects or increase in walking capacity were detected.. Inhibition of XO by oxypurinol in patients with CHF decreases SUA and improves LVEF in patients with LVEF < or = 40% after 1 month of treatment.

Topics: Aged; Double-Blind Method; Enzyme Inhibitors; Female; Heart Failure; Humans; Male; Oxypurinol; Physical Endurance; Stroke Volume; Uric Acid; Walking; Xanthine Oxidase

Oxypurinol, the active metabolite of allopurinol and a potent xanthine oxidase inhibitor (XOI), is under evaluation as a novel agent for the treatment of congestive heart failure (HF). Several lines of evidence provide the rationale for the hypothesis that XOIs will improve clinical outcomes in patients with HF. First, XOIs have unique positive inotropic effects, improving myocardial contraction and performance while simultaneously improving myocardial energy metabolism. Second, XOIs ameliorate endothelial dysfunction in humans with HF. Finally, XO activity is upregulated in the heart and vasculature of subjects with HF, which may in turn contribute to oxidative stress and/or increased uric acid levels. Together these findings form the rationale for the Controlled Efficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients with New York Heart Association (NYHA) class III - IV Congestive Heart Failure (OPT-CHF) trial (Food and Drug Administration IND 65,125), a Phase II - III prospective, randomised, double-blind, placebo-controlled trial, which will include patients with stable symptomatic HF in NYHA class III - IV congestive HF who are deemed clinically stable on a standard and appropriately maximised heart failure therapy regimen. The efficacy end point for OPT-CHF is a composite that incorporates measures of patient outcome and well-being.

Topics: Double-Blind Method; Heart Failure; Humans; Oxypurinol; Research Design; Xanthine Oxidase

Topics: Dose-Response Relationship, Drug; Heart Failure; Humans; Oxypurinol; Xanthine Oxidase

Previously, we showed that oral allopurinol increased survival in mice with post-ischemic cardiomyopathy and attributed this outcome to an improvement of excitation-contraction coupling that boosted contractility. In this study, we tested the sustainability of this enhanced contraction associated with decreased oxidative damage over an extended time. Mice were divided into three groups: sham-operated control, myocardial infarction-heart failure (MI-HF), and oxypurinol-treated heart failure (Oxy-HF). After 9-11 months, echocardiography showed that mice treated with oxypurinol (1mM in drinking water) had significantly higher left ventricle fractional contraction and fractional wall thickening during systole than did mice in the MI-HF group (left ventricle fractional contraction: 28.4+/-2.2% vs. 19.9+/-2.3%, P<0.05; left ventricle fractional wall thickening: 45.0+/-4.0% vs. 23.5+/-2.0%, P<0.05). Left ventricular diastolic dimension, however, remained enlarged (0.50+/-0.04 vs. 0.54+/-0.05 cm, not significant). Twitch force was significantly higher at any given external Ca(2+) concentration in the Oxy-HF group than in the MI-HF group (P<0.01); amplitudes of intracellular Ca(2+) transients were also higher in the Oxy-HF group but were not statistically different from those of the MI-HF group. Force-frequency relation was improved in the Oxy-HF group. Muscle in the Oxy-HF group exhibited increases in myofilament Ca(2+) responsiveness, as evidenced by significantly higher maximal Ca(2+)-activated force (77.8+/-12.7 vs. 36.4+/-4.4 mN/mm(2), P<0.01). Finally, lipid peroxidation and myofilament oxidation were suppressed in the Oxy-HF group. These results indicate that the beneficial effects of antioxidation can be sustained by long-term treatment with oxypurinol after ischemic heart failure, with significantly improved cardiac contractility.

Topics: Animals; Calcium; Enzyme Inhibitors; Excitation Contraction Coupling; Heart; Heart Failure; Male; Mice; Myocardial Contraction; Myocardial Ischemia; Myocardium; Oxidation-Reduction; Oxidative Stress; Oxypurinol; Time Factors; Xanthine Oxidase

Topics: Enzyme Inhibitors; Heart Failure; Humans; Natriuretic Peptide, Brain; Oxypurinol; Risk Factors; Systole; Uric Acid; Xanthine Oxidase

Topics: Allopurinol; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Kidney Diseases; Oxidative Stress; Oxypurinol; Uric Acid

Increased reactive oxygen species (ROS) generation is implicated in cardiac remodeling in heart failure (HF). As xanthine oxidoreductase (XOR) is 1 of the major sources of ROS, we tested whether XOR inhibition could improve cardiac performance and induce reverse remodeling in a model of established HF, the spontaneously hypertensive/HF (SHHF) rat. We randomized Wistar Kyoto (WKY, controls, 18 to 21 months) and SHHF (19 to 21 months) rats to oxypurinol (1 mmol/L; n=4 and n=15, respectively) or placebo (n=3 and n=10, respectively) orally for 4 weeks. At baseline, SHHF rats had decreased fractional shortening (FS) (31+/-3% versus 67+/-3% in WKY, P<0.0001) and increased left-ventricular (LV) end-diastolic dimension (9.7+/-0.2 mm versus 7.0+/-0.4 mm in WKY, P<0.0001). Whereas placebo and oxypurinol did not change cardiac architecture in WKY, oxypurinol attenuated decreased FS and elevated LV end-diastolic dimension, LV end-systolic dimension, and LV mass in SHHF. Increased myocyte width in SHHF was reduced by oxypurinol. Additionally, fetal gene activation, altered calcium cycling proteins, and upregulated phospho-extracellular signal-regulated kinase were restored toward normal by oxypurinol (P<0.05 versus placebo-SHHF). Importantly, SHHF rats exhibited increased XOR mRNA expression and activity, and oxypurinol treatment reduced XOR activity and superoxide production toward normal, but not expression. On the other hand, NADPH oxidase activity remained unchanged, despite elevated subunit protein abundance in treated and untreated SHHF rats. Together these data demonstrate that chronic XOR inhibition restores cardiac structure and function and offsets alterations in fetal gene expression/Ca2+ handling pathways, supporting the idea that inhibiting XOR-derived oxidative stress substantially improves the HF phenotype.

Topics: Animals; Calcium-Transporting ATPases; Cardiomyopathy, Dilated; Enzyme Inhibitors; Gene Expression; Heart Failure; Myocardium; NADPH Oxidases; Oxidative Stress; Oxypurinol; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Remodeling; Xanthine Oxidase

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the Heart Failure Society of America meeting held in Seattle in September 2006. All reports should be considered as preliminary data, as analyses may change in the final publication. Devices designed to improve cardiac contractility may have improved exercise tolerance and quality of life in the FIX-CHF-4 study; however, uncertainties in trial interpretation exist. The results of a study reporting the first administration of the selective myosin activator CK-1827452 to human volunteers, support the initiation of clinical trials in heart failure patients. In OPT-CHF, oxypurinol failed to show benefit compared to placebo for the treatment of heart failure, although a retrospective subgroup analysis suggests that it may be beneficial in patients with elevated serum uric acid levels.

Topics: Cardiotonic Agents; Clinical Trials as Topic; Enzyme Inhibitors; Heart Failure; Heart-Assist Devices; Humans; Oxypurinol

The plasma level of the uric acid is frequently elevated in heart failure, due to increased production and/or to reduced renal excretion of this antioxidant metabolite. The transformation of hypoxanthine to xanthine and the conversion of the latter into uric acid, which occur in purine catabolism, are catalysed by xanthine oxidoreductase. The constitutive xanthine dehydrogenase form of this enzyme generally uses NAD(+) as an electron acceptor, whereas the post-translational xanthine oxidase form uses molecular oxygen and yields four units of reactive oxygen species per unit of transformed substrate. Allopurinol and oxypurinol inhibit xanthine oxidoreductase and thus diminish the generation of reactive species and decrease plasma uric acid. In a recent study in patients with NHYA class II-III heart failure, add-on treatment with allopurinol 300 mg/day for 3 months lowered plasma uric acid but failed to improve laboratory exercise performance or the distance walked in 6 minutes. In another recent trial, which was carried out in patients with NHYA class III-IV heart failure, add-on treatment with oxypurinol 600 mg/day for 24 weeks decreased plasma uric acid concentration but did not change a composite of patient outcome and state. These results indicate that the reduction in plasma uric acid caused by allopurinol or oxypurinol does not benefit patients with heart failure. Moreover, the hypothesis that the diminution in the renal excretion of the antioxidant uric acid caused by diuretics may be salutary in cardiac failure is strengthened by the study results considered.

Topics: Allopurinol; Antioxidants; Enzyme Inhibitors; Heart Failure; Humans; Oxypurinol; Randomized Controlled Trials as Topic; Uric Acid; Xanthine Oxidase

Topics: Allopurinol; Animals; Enzyme Inhibitors; Free Radicals; Heart Failure; Humans; Models, Animal; Myocardium; Oxygen; Oxypurinol; Rats; Xanthine Oxidase

Xanthine oxidase (XO) inhibitors enhance myofilament Ca(2+) responsiveness of normal rat myocardium. We examined whether this inotropic action is preserved or magnified in failing rat myocardium and whether the magnitude of this effect correlates with tissue xanthine-oxidoreductase (XOR) activity.. Hearts of 18-20 month-old SHHF (spontaneous hypertensive/heart failure) rats with end-stage heart failure, as well as of normal control rats, were perfused with the XO inhibitor oxypurinol. Afterwards, [Ca(2+)](i) and tension were measured simultaneously in fura-2-loaded intact isolated right ventricular trabeculae. XOR activity was determined fluorometrically in myocardial homogenates.. In failing myocardium, 100 microM oxypurinol significantly increased systolic twitch tension (by 87 and 92% at 1.0 and 1.5 mM extracellular [Ca(2+)], respectively), without altering [Ca(2+)](i) transient amplitude. Oxypurinol did not alter the midpoint or cooperativity of the steady-state tension-[Ca(2+)](i) relationship, but significantly enhanced maximum Ca(2+)-activated tension by 75% in failing myocardium. Oxypurinol also exerted a positive inotropic effect in failing myocardium, which was, however, of significantly smaller relative magnitude. Failing rat myocardium exhibited higher XOR activity than nonfailing myocardium, and this activity was largely suppressed in oxypurinol-treated preparations.. The magnitude of functional improvement with XOR inhibitors depends on the initial level of XOR activity. Specifically, the inotropic actions of oxypurinol are more pronounced in failing rat myocardium, a tissue that exhibits enhanced XOR activity. Our findings rationalize how XO inhibitors boost cardiac contractility and improve mechanoenergetic coupling, and why the effects might be relatively 'selective' for heart failure.

Topics: Animals; Enzyme Inhibitors; Heart Failure; Hypertension; In Vitro Techniques; Male; Myocardial Contraction; Myocardium; Oxypurinol; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WF; Receptors, Cell Surface; Receptors, Leptin; Stimulation, Chemical; Xanthine Oxidase