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)

Polyethylene glycol-modified urate oxidase (PEG-uricase) holds promise as a hypouricemic agent for treating gout and as an adjunct to cytolytic therapy of hematologic malignancies. Spectrophotometric assays of urate oxidase are not sensitive enough for pharmacokinetic evaluation of PEG-uricase in clinical trials. We have therefore developed a more sensitive radiochemical-HPLC assay for urate oxidase activity in untreated plasma, in which 14C in urate and in the reaction product, allantoin, is monitored in the uv detector effluent with a flow-through scintillation counter. The assay is linear with amount of enzyme and time of incubation and can detect less than 1 x 10(-5) U/ml uricase in plasma. The assay accounts for plasma samples of widely differing urate content.
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PMID:A radiochemical-high-performance liquid chromatographic assay for urate oxidase in human plasma. 274 21

Immune triggered granulocyte (PMN)-endothelial interactions have been implicated in the pathogenesis of vascular diseases. While hyperuricemia and gout are associated with an increased risk of atherogenesis, we studied the modulation by monosodium-urate (MSU) crystals of PMN-endothelial interactions in vitro. The relationship between calcium oxalate (COX) crystals - implicated in the vasculitis of primary oxalosis - and immunologically mediated endothelial injury was also explored. Both MSU- and COX-crystal treated sera stimulate PMN to adhere to and induce significant 51Cr-release from endothelial cells in vitro. Platelets significantly increase crystal-triggered PMN endothelial cell adherence and 51Cr-release. This platelet augmenting effect depends on the release of platelet constituents (e.g. serotonin). Microcrystalline material present in vessel walls, thus may cause C-activation and may trigger PMN and platelets to damage endothelium in vitro and in vivo. These findings may have relevance to the understanding of the accelerated atherogenesis of hyperuricemia and the fulminant vasculitis of oxalosis or ethylene glycol poisoning.
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PMID:Mechanisms of vascular damage in gout and oxalosis: crystal induced, granulocyte mediated, endothelial injury. 663 34

The C1q agglutination-inhibition test (C1q-AIT) is a sensitive assay, capable of detecting circulating immune complexes (CIC) containing as little as 40 ng C1q. This non-isotopic test can be easily performed in 4 h from the receipt of the serum sample (including the isolation of CIC by PEG 6000 percipitation). The reagents are stable for at least 6 months under normal refrigeration. Because a carefully standardized C1q- anti-C1q reaction is used, CIC can be semi-quantitated by a routine titration procedure. Sera from patients with diseases reported to be associated with CIC gave significantly high test results, while diseases not normally associated with CIC (e.g. OA, gout, allergy) gave low frequencies of positive results. The C1q-AIT for CIC containing endogenously bound C1q was shown to be equivalent to and more sensitive than the [125I]C1q-BA for CIC containing exogenously bound C1q.
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PMID:A new capillary tube agglutination-inhibition test for the detection of circulating immune complexes containing endogenously bound C1q. 726 15

Uricase-deficient mice develop uric acid nephropathy, with high mortality rates before weaning. Urate excretion was quantitated and renal function was better defined in this study, to facilitate the use of these mice as a model for evaluating poly(ethylene glycol)-modified recombinant mammalian uricases (PEG-uricase) as a potential therapy for gout and uric acid nephropathy. The uric acid/creatinine ratio in the urine of uricase-deficient mice ranges from 10 to >30; on a weight basis, these mice excrete 20- to 40-fold more urate than do human subjects. These mice consistently develop a severe defect in renal concentrating ability, resulting in an approximately sixfold greater urine volume and a fivefold greater fluid requirement, compared with normal mice. This nephrogenic diabetes insipidus leads to dehydration and death of nursing mice but, with adequate water replacement, high urine flow protects adults from progressive renal damage. Treatment of uricase-deficient mice with PEG-uricase markedly reduced urate levels and, when initiated before weaning, preserved the renal architecture (as evaluated by magnetic resonance micros-copy) and prevented the loss of renal concentrating function. PEG-uricase was far more effective and less immunogenic than unmodified uricase. Retention of uricase in most mammals and its loss in humans and some other primates may reflect the evolution of renal function under different environmental conditions. PEG-uricase could provide an effective therapy for uric acid nephropathy and refractory gout in human patients.
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PMID:Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase. 1131 59

PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout), whose plasma uric acid concentration (pUAc) was 11.3 +/- 2.1 mg/dl (mean +/- SD). By day seven after injection of PEG-uricase, pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 +/- 2.2 mg/dl. At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for other PEGylated therapeutic agents in clinical use.
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PMID:Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. 1635 99

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

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

Urate oxidase catalyzes the oxidation of uric acid with poor solubility to produce 5-hydroxyisourate and allantoin. Since allantoin is excreted in vivo, urate oxidase has the potential to be a therapeutic target for the treatment of gout. However, its severe immunogenicity limits its clinical application. Furthermore, studies on the structure-function relationships of urate oxidase have proven difficult. We developed a method for genetically incorporating p-azido-L-phenylalanine into target protein in Escherichia coli in a site-specific manner utilizing a tyrosyl suppressor tRNA/aminoacyl-tRNA synthetase system. We substituted p-azido-L-phenylalanine for Phe(170) or Phe(281) in urate oxidase. The products were purified and their enzyme activities were analyzed. In addition, we optimized the system by adding a "Shine-Dalgarno (SD) sequence" and tandem suppressor tRNA. This method has the benefit of site-specifically modifying urate oxidase with homogeneous glycosyl and PEG derivates, which can provide new insights into structure-function relationships and improve pharmacological properties of urate oxidase.
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PMID:Site-specific incorporation of unnatural amino acids into urate oxidase in Escherichia coli. 1859 2

Gout is the most common form of inflammatory arthritis in the elderly. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into the transporters that handle uric acid in the kidney as well as possible links between these transporters, hyperuricemia, and hypertension. The treatment of established hyperuricemia has also seen new developments. Febuxostat and PEG-uricase are two novel treatments that have been evaluated and shown to be highly effective in the management of hyperuricemia, thus enlarging the therapeutic options available to lower uric acid levels. Monosodium urate (MSU) crystals are potent inducers of inflammation. Within the joint, they trigger a local inflammatory reaction, neutrophil recruitment, and the production of pro-inflammatory cytokines as well as other inflammatory mediators. Experimentally, the uptake of MSU crystals by monocytes involves interactions with components of the innate immune system, namely Toll-like receptor (TLR)-2, TLR-4, and CD14. Intracellularly, MSU crystals activate multiple processes that lead to the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome complex that in turn processes pro-interleukin (IL)-1 to yield mature IL-1 beta, which is then secreted. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances in the understanding of hyperuricemia and gout provide new therapeutic targets for the future.
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PMID:Developments in the scientific and clinical understanding of gout. 1894 74


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