Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gout is a common chronic arthritis that can lead to significant disability. Gout is one of the few rheumatological conditions that can be diagnosed with certainty, has a known cause and can be cured with appropriate therapy. Hypouricaemic agents reduce uric acid concentrations through inhibiting uric acid production (allopurinol) or enhancing uric acid excretion (probenecid, benzbromarone). Allopurinol is the most commonly used hypouricaemic agent but at recommended doses often fails to reduce adequately uric acid concentrations and prevent acute attacks of gout. The use of probenecid is limited by lack of efficacy in renal impairment. In the last few years, new agents in the management of hyperuricaemia and gout have become available. Febuxostat, a new xanthine oxidase inhibitor, is an effective hypouricaemic agent although further data are required for patients with renal impairment and other significant medical conditions. Rasburicase, a recombinant uricase (which catalyses the conversion of uric acid to the more readily excreted allantoin) is available for prevention of tumour lysis syndrome. However, its repeated use, as would be required in chronic gout, is limited by antigenicity. A less antigenic PEGylated uricase can rapidly reduce serum uric acid concentrations and promote resorption of tophi. However, further information with regard to the long-term risks and benefits of these agents is required. These agents may ultimately be used in the short term to rapidly deplete urate stores (induction therapy) followed by long-term therapy with an alternative hypouricaemic agent to prevent subsequent accumulation of uric acid (maintenance therapy).
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PMID:Emerging therapies in the long-term management of hyperuricaemia and gout. 1738 67

Hyperuricemia is a feature of several pathologies and requires an appropriate and often early treatment, owing to the severe consequences that it may cause. A rapid and massive raise of uric acid, during tumor lysis syndrome (TLS), and also a lower and chronic hyperuricemia, as in gout, mainly damage the kidney. To prevent or treat these consequences, a new therapeutic option is represented by rasburicase, a recombinant form of an enzyme, urate oxidase. This enzyme converts hypoxanthine and xanthine into allantoin, a more soluble molecule, easily cleared by kidney. The several types of urate oxidase have followed each other, with progressive reduction of adverse reactions. The most important among them are allergenicity and the development of antibodies which compromise their effectiveness. Nevertheless, a limit of rasburicase's use remains its cost, which obliges to a judicious choice to prevent TLS in high risk patients with cancer and in case of allergy or impossibility to take allopurinol orally both in TLS and in gout. A large body of evidence confirms the efficacy and safety of rasburicase, even in comparison to the standard drugs used in the aforementioned pathologies.
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PMID:Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. 1739 59

Successful management of chronic gout depends on reducing body pools of urate. The benchmark of success is to maintain serum urate levels at less than 6 mg/dL using therapies such as probenecid or allopurinol. In a subset of patients with gout, these medications fail to achieve this benchmark, resulting in ongoing signs and symptoms characteristic of treatment-failure gout. Potential therapies now in clinical development show promise for treating this refractory patient population. In this article, we review the clinical characteristics associated with treatment-failure gout and discuss recent data from clinical trials of febuxostat and uricase.
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PMID:Uricase and other novel agents for the management of patients with treatment-failure gout. 1753 Nov 81

There has been renewed interest in the treatment of gout with recent reported intervention studies of new agents such as etoricoxib, febuxostat and pegylated-uricase. However, these studies have highlighted the relative paucity of validated outcome measures with which to judge efficacy. This review outlines the published information regarding which endpoints have been measured in randomized clinical trials, what should be measured, what tools or instruments are available for this and the technical properties of such instruments. It highlights recent work that validates measures of tophi, radiographic damage and patient-reported outcomes. The absence of a valid definition of gout-flare or how flare reduction defines response is problematic; this forms the basis for a current ACR-EULAR sponsored project.
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PMID:Assessment of outcome in clinical trials of gout--a review of current measures. 1765 May 21

Hyperuricemia results from an imbalance between the rates of production and excretion of uric acid. Longstanding hyperuricemia can lead to gout, which is characterized by the deposition of monosodium urate monohydrate crystals in the joints and periarticular structures. Because such deposits are resolved very slowly by lowering plasma urate with available drugs or other measures, the symptoms of gout may become chronic. Persistent hyperuricemia may also increase the risk of renal and cardiovascular diseases. Unlike most mammals, humans lack the enzyme uricase (urate oxidase) that catalyzes the oxidation of uric acid to a more soluble product. This review describes the development of a poly(ethylene glycol) (PEG) conjugate of recombinant porcine-like uricase with which a substantial and persistent reduction of plasma urate concentrations has been demonstrated in a Phase 2 clinical trial. Two ongoing Phase 3 clinical trials include systematic assessments of gout symptoms, tophus resolution and quality of life, in addition to the primary endpoint of reduced plasma urate concentration.
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PMID:PEG-uricase in the management of treatment-resistant gout and hyperuricemia. 1782 65

Over the past decade, significant advances have been made regarding the pathogenesis, clinical implications, and treatment of hyperuricemia. While physicians have understood for at least a century that uric acid causes gout, we are now beginning to address the question of why hyperuricemia exists and the mechanisms by which uric acid acts to stimulate inflammation. This review focuses on (1) previously unknown biological roles of uric acid; (2) why the loss of the uricase gene and resultant hyperuricemia may have provided an evolutionary advantage to primates and, in particular, to humans; (3) the molecular effects of uric acid on inflammatory cells; and (4) novel antihyperuricemic agents currently under study.
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PMID:Hyperuricemia and gout: new insights into pathogenesis and treatment. 1792 73

After several decades of senescence, the twin fields of hyperuricemia and gout have again regained attention in both the scientific and clinical spheres, and this review highlights several recent advancements. Specifically, we review newly discovered mechanisms of uric acid-induced inflammation, uric acid's putative role as a "danger signal" in innate immunity, the possible link between hyperuricemia and cardiovascular disease, and evolutionary evidence suggesting that hyperuricemia conferred a survival advantage in primates (when the gene for uricase was lost) several million years ago. Finally, we provide an overview of the current approach to gout, as well as what treatments are on the horizon.
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PMID:Update on gout: pathophysiology and potential treatments. 1817 79

Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
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PMID:SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. 1832 57

Savient Pharmaceuticals Inc (formerly Bio-Technology General Corp), under license from Duke University, is developing pegloticase, PEG conjugates of uricase (urate oxidase), for the potential treatment of gout. The in-life portion of the phase III trials have been completed.
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PMID:Pegloticase, a polyethylene glycol conjugate of uricase for the potential intravenous treatment of gout. 1839 9

An inhibitor of xanthine dehydrogenase (XDH), allopurinol, and uricosuric agents, probenecid and benzbromarone, have been used for more than 20 years in the treatment of hyperuricemia and gout. However, they are inconvenient in some situations. With regard to allopurinol, the dosage reduction is recommended in patients with renal insufficiency for preventing from rare adverse effect, bone marrow depression. Benzbromarone also has quite rare adverse effect, fulminant hepatitis. Recently several new therapies have been developed such as new XDH inhibitors urate transporter (URAT) 1 inhibitor, and a modified recombinant uricase. The dosage reduction of the new XDH inhibitors, febuxostat and FYX-051, is not necessary in patients with renal insufficiency because renal excretion is not main excretory pathway. JTT-552 is a first medicine targeting on URAT1. Polyethylene glycol (PEG) conjugation with recombinant uricase sufficiently reduces the immunogenicity to permit repeated dosing and the clinical trials are ongoing for patients with treatment-failure gout and hyperuricemia.
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PMID:[New antihyperuricemic medicine: febuxostat, Puricase, etc]. 1840 28


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