UMLS:C0018801 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gout in the elderly differs from classical gout found in middle-aged men in several respects: it has a more equal gender distribution, frequent polyarticular presentation with involvement of the joints of the upper extremities, fewer acute gouty episodes, a more indolent chronic clinical course, and an increased incidence of tophi. Long term diuretic use in patients with hypertension or congestive cardiac failure, renal insufficiency, prophylactic low dose aspirin (acetylsalicylic acid), and alcohol (ethanol) abuse (particularly by men) are factors associated with the development of hyperuricaemia and gout in the elderly. Extreme caution is necessary when prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute gouty arthritis in the elderly. NSAIDs with short plasma half-life (such as diclofenac and ketoprofen) are preferred, but these drugs are not recommended in patients with peptic ulcer disease, renal failure, uncontrolled hypertension or cardiac failure. Colchicine is poorly tolerated in the elderly and is best avoided. Intra-articular and systemic corticosteroids are increasingly being used for treating acute gouty flares in aged patients with medical disorders contraindicating NSAID therapy. Urate-lowering drugs are indicated for the treatment of hyperuricaemia and chronic gouty arthritis. Uricosuric drugs are poorly tolerated and the frequent presence of renal impairment in the elderly renders these drugs ineffective. Allopurinol is the urate-lowering drug of choice, but its use in the aged is associated with an increased incidence of both cutaneous and severe hypersensitivity reactions. To minimise this risk, allopurinol dose must be kept low. A starting dose of allopurinal 50 to 100mg on alternate days, to a maximum daily dose of about 100 to 300mg, based upon the patient's creatinine clearance and serum urate level, is recommended. Asymptomatic hyperuricaemia is not an indication for long term urate-lowering therapy; the risks of drug toxicity often outweigh any benefit.
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PMID:Gout in the elderly. Clinical presentation and treatment. 978 27

Allopurinol, an inhibitor of xanthine oxidase, increases myofilament calcium responsiveness and blunts calcium cycling in isolated cardiac muscle. We sought to extend these observations to conscious dogs with and without pacing-induced heart failure and tested the prediction that allopurinol would have a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. In control dogs (n=10), allopurinol (200 mg IV) caused a small positive inotropic effect; (dP/dt)(max) increased from 3103+/-162 to 3373+/-225 mm Hg/s (+8.3+/-3.2%; P=0.01), but preload-recruitable stroke work and ventricular elastance did not change. In heart failure (n=5), this effect was larger; (dP/dt)(max) rose from 1602+/-190 to 1988+/-251 mm Hg/s (+24.4+/-8.7%; P=0.03), preload-recruitable stroke work increased from 55.8+/-9.1 to 84. 9+/-12.2 mm Hg (+28.1+/-5.3%; P=0.02), and ventricular elastance rose from 6.0+/-1.6 to 10.5+/-2.2 mm Hg/mm (P=0.03). Allopurinol did not affect myocardial lusitropic properties either in control or heart failure dogs. In heart failure dogs, but not controls, allopurinol decreased myocardial oxygen consumption (-49+/-4.6%; P=0. 002) and substantially increased mechanical efficiency (stroke work/myocardial oxygen consumption; +122+/-42%; P=0.04). Moreover, xanthine oxidase activity was approximately 4-fold increased in failing versus control dog hearts (387+/-125 versus 78+/-72 pmol/min. mg(-1); P=0.04) but was not detectable in plasma. These data indicate that allopurinol possesses unique inotropic properties, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of congestive heart failure.
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PMID:Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure. 1047 73

Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism. We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the +26.2+/-3.5% and +66.5+/-17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MVO2) while lowering left ventricular external work, reducing efficiency by 31.1+/-3.8% (P<0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure.
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PMID:Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. 1186 18

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 had exercised its option to acquire from ILEX Oncology Inc. rights to clinical trial data for oxypurinol for the treatment of gout in allopurinol-intolerant patients. ILEX completed its open-label phase II clinical study of Oxyprim in allopurinol-intolerant gout patients, and the trial data were transferred to Cardiome. Cardiome stated in May 2002 that it intended to commence a further phase II trial of oxypurinol in gout. Phase III trials were in progress in 2003 in this indication. In 1995, ILEX Oncology continued the compassionate use distribution of oxipurinol while establishing a US FDA-approved registration plan for the agent. In November 1998, ILEX received Orphan Drug status for the use of oxipurinol in patients with symptomatic hyperuricaemia. ILEX Oncology's Development Pipeline for 1998 stated that oxipurinol had entered phase II clinical trials for the treatment of hyperuricaemia. In 2001, the clinical trials listing service CenterWatch stated that oxipurinol was in a phase II clinical trial with ILEX Oncology for the treatment of symptomatic hyperuricaemia in patients who are intolerant to allopurinol. The trial appeared to be taking place in the US, and was a multicentre, open-label, 14-week study in 90 patients. In February 2003, Cardiome confirmed beginning patient enrollment in three smaller phase II studies, with the first trial (EXOTIC) now completed. These three smaller proof-of-concept studies will observe surrogate endpoints such as cardiac output and exercise tolerance. The second proof-of-concept study in patients with CHF of ischemic aetiology (IV), known as EXOTIC-EF (Evaluation of XanThine Oxidase Inhibition on Cardiac Ejection Fraction), will assess the effects of oxypurinol on left ventricular performance. The EXOTIC-EF trial will start in the first quarter of 2004 and be completed by the second quarter of 2004. The third, LA PLATA, proof-of-concept study will explore the effects of 1 month of oral oxypurinol therapy on exercise capacity and left ventricular performance. It is projected that the LA PLATA study will start in the first quarter of 2004 and be completed by the third quarter of 2004. During the Heart Failure Society of America's meeting on 21 September 2003, Cardiome presented clinical data from its first proof-of-concept EXOTIC (European Xanthine Oxidase Inhibitors Trial In Cardiac Disease) study. Cardiome intends to conduct a second trial, at the Eppendorf Clinic at the University of Hamburg, to determine the effect of oxypurinol on left ventricular performance in patients with CHF of ischaemic aetiology. This study will be an extension of the original proof-of-concept study. According to the 1st Annual BioPartnering conference held in Vancouver, Canada, in February 2003, Cardiome is seeking co-development partners for oxipurinol in the treatment of congestive heart failure. In July 2003, the US Patent and Trademark Office issued a new patent providing additional protection to Cardiome's programme focused on treatment of congestive heart failure with oxypurinol. The patent, No. 6,569,862, was the second issued to the Johns Hopkins University (JHU) in this field. The key claims in the new patent cover use of the entire family of drugs known as xanthine oxidase inhibitors applied to contractile disorders of the heart, including congestive heart failure. An earlier patent issued to JHU contained provisions relating to a specific mechanism of action and to specific forms of heart disease. Both patents and related intellectual property are licensed exclusively to Cardiome.
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PMID:Oxipurinol: alloxanthine, Oxyprim, oxypurinol. 1513 81

Heart failure is a clinical syndrome associated with elevated levels of oxygen-derived free radicals. Xanthine oxidase activity is believed to be one source of reactive oxygen species in the failing heart. Interventions designed to reduce oxidative stress are believed to have significant therapeutic potential in heart failure. This study tested the hypothesis that xanthine oxidase activity would be elevated in a mouse model of dilated cardiomyopathy and evaluated the effect of chronic oral allopurinol, an inhibitor of xanthine oxidase, on contractility and progressive ventricular dilation in these mice. Nontransgenic and transgenic mice containing a troponin I truncation were treated with oral allopurinol from 2-4 mo of age. Myocardial xanthine oxidase activity was threefold higher in untreated transgenic mice compared with nontransgenic mice. Analyses of myofilament proteins for modification of carbonyl groups demonstrated myofibrillar protein damage in untreated transgenic mice. Treatment with allopurinol for 2 mo suppressed xanthine oxidase activity and myofibrillar protein oxidation. Allopurinol treatment also alleviated ventricular dilation and preserved shortening fraction in the transgenic animals. In addition, cardiac muscle twitch tension was preserved to 70% of nontransgenic levels in allopurinol-treated transgenic mice, a significant improvement over untreated transgenic mice. These findings indicate that chronic inhibition of xanthine oxidase can alter the progression of heart failure in dilated cardiomyopathy.
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PMID:Chronic xanthine oxidase inhibition prevents myofibrillar protein oxidation and preserves cardiac function in a transgenic mouse model of cardiomyopathy. 1586 59

We hypothesized that chronic xanthine oxidase inhibition (XOI) would have favorable effects on both ventricular and vascular performance in evolving heart failure (HF), thereby preserving ventricular-vascular coupling. In HF, XOI reduces oxidative stress and improves both vascular and myocardial function. Dogs were randomized to receive either allopurinol (100 mg/day p.o.) or placebo following surgical instrumentation for chronic measurement of left-ventricular pressure and dimension and during induction of HF by rapid pacing. In the placebo group (n = 8), HF was characterized by increased LV end-diastolic pressure (LVEDP, 10.2 +/- 5.5 and 29.8 +/- 3.9 mmHg, before and after HF, respectively, P < 0.05), end-diastolic dimension (LVEDD, from 29.5 +/- 3.2 to 34.3 +/- 3.2 mm, P < 0.001), and afterload (arterial elastance, Ea, from 17.9 +/- 1.2 to 42.6 +/- 7.9 mmHg/mm, P < 0.05), and reduced contractility (End-systolic ventricular elastance, Ees, from 10.8 +/- 1.3 to 5.6 +/- 2.3 mmHg/mm, P < 0.05). Thus, ventricular-vascular coupling (Ees/Ea ratio) fell 57.6+/-9% (0.61 +/- 0.1 to 0.16 +/- 0.1, P < 0.05). Allopurinol (n = 9) profoundly attenuated both the Ea increase (from 22.3 +/- 3 to 25.6 +/- 4.6 mmHg/mm, P = NS) and the fall in Ees (from 11.8+/-1.1 to 11.7+/-1, P = NS), thereby preserving the Ees/Ea ratio (from 0.58 +/- 0.1 to 0.56 +/- 0.1, P < 0.001 vs. placebo). Allopurinol did not affect the increase in preload (LVEDP and LVEDD). XO cardiac mRNA and protein were similarly upregulated approximately fourfold in both groups. Allopurinol ameliorates increases in afterload and reductions in myocardial contractility during evolving HF, thereby preserving ventricular-vascular coupling. These results demonstrate a unique and potent hemodynamic profile of XOI, thereby providing further rationale for developing XOIs as a novel HF therapy.
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PMID:Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure. 1597 9

Oxidative stress is one of the new and most intriguing pathogenetic hypotheses of heart failure; it involves various mechanisms such as endothelial dysfunction, mechano-energetic uncoupling and apoptosis. Xanthine oxidase, a key enzyme in purine catabolism, is overexpressed in patients with heart failure, and it is also an important source of oxidizing activity molecules (free radicals, superoxide anion, oxygen peroxide, etc...). Allopurinol competitively inhibits the action of xanthine oxidase and effectively counters oxidative stress. It could thus prove useful in the treatment of heart failure: in fact it is the only drug that has been proven able to lower O2 consumption of dysfunctioning myocardium. The Authors briefly review the xanthine oxido-reductase enzyme system and in particular analyse the latest evidence reported in the literature on allopurinol in the treatment of heart failure.
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PMID:Heart failure, oxidative stress and allopurinol. 1612 62

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.
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PMID:Allopurinol or oxypurinol in heart failure therapy - a promising new development or end of story? 1638 92

The prototypical xanthine oxidase (XO) inhibitor allopurinol, has been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades. More recent data indicate that XO also plays an important role in various forms of ischemic and other types of tissue and vascular injuries, inflammatory diseases, and chronic heart failure. Allopurinol and its active metabolite oxypurinol showed considerable promise in the treatment of these conditions both in experimental animals and in small-scale human clinical trials. Although some of the beneficial effects of these compounds may be unrelated to the inhibition of the XO, the encouraging findings rekindled significant interest in the development of additional, novel series of XO inhibitors for various therapeutic indications. Here we present a critical overview of the effects of XO inhibitors in various pathophysiological conditions and also review the various emerging therapeutic strategies offered by this approach.
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PMID:Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. 1650 84

Myocardial oxidative stress and Ca2+ overload induced by ischemia-reperfusion may be involved in the development and progression of myocardial dysfunction in heart failure. Xanthine oxidase, which is capable of producing reactive oxygen species, is considered as a culprit regarding ischemia-reperfusion injury of cardiomyocytes. Even though inhibition of xanthine oxidase by allopurinol in failing hearts improves cardiac performance, the regulatory mechanisms are not known in detail. We therefore hypothesized that allopurinol may prevent the xanthine oxidase-induced reactive oxygen species production and Ca2+ overload, leading to decreased calcium-responsive signaling in myocardial dysfunction. Allopurinol reversed the increased xanthine oxidase activity in ischemia-reperfusion injury of neonatal rat hearts. Hypoxia-reoxygenation injury, which simulates ischemia-reperfusion injury, of neonatal rat cardiomyocytes resulted in activation of xanthine oxidase relative to that of the control, indicating that intracellular xanthine oxidase exists in neonatal rat cardiomyocytes and that hypoxia-reoxygenation induces xanthine oxidase activity. Allopurinol (10 microM) treatment suppressed xanthine oxidase activity induced by hypoxia-reoxygenation injury and the production of reactive oxygen species. Allopurinol also decreased the concentration of intracellular Ca2+ increased by enhanced xanthine oxidase activity. Enhanced xanthine oxidase activity resulted in decreased expression of protein kinase C and sarcoendoplasmic reticulum calcium ATPase and increased the phosphorylation of extracellular signal-regulated protein kinase and p38 kinase. Xanthine oxidase activity was increased in both ischemia-reperfusion-injured rat hearts and hypoxia-reoxygenation-injured cardiomyocytes, leading to reactive oxygen species production and intracellular Ca2+ overload through mechanisms involving p38 kinase and extracellular signal-regulated protein kinase (ERK) via sarcoendoplasmic reticulum calcium ATPase (SERCA) and protein kinase C (PKC). Xanthine oxidase inhibition with allopurinol modulates reactive oxygen species production and intracellular Ca2+ overload in hypoxia-reoxygenation-injured neonatal rat cardiomyocytes.
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PMID:Allopurinol modulates reactive oxygen species generation and Ca2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes. 1651 85

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