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)

THE CONCEPT OF AN ABNORMALITY OF GLUTAMINE METABOLISM IN PRIMARY GOUT WAS FIRST PROPOSED ON THE BASIS OF ISOTOPE DATA: when [(15)N]glycine was administered to gouty subjects, there was disproportionately great enrichment of N-(3 + 9) of uric acid, which derive from the amide-N of glutamine. An unduly high concentration of (15)N in glutamine was postulated, and attributed to a hypothetical defect in catabolism of glutamine. Excess glutamine was proposed as the driving force of uric acid overproduction. WE HAVE REEXAMINED THIS PROPOSITION IN FOUR GOUTY SUBJECTS: one mild overproducer of uric acid with "idiopathic gout," one marked overproducer with high-grade but "partial" hypoxanthine-guanine phosphoribosyl-transferase deficiency, and two extraordinary overproducers with superactive phosphoribosylpyrophosphate synthetases. In the last three, the driving force of excessive purine biosynthesis is a known surplus of alpha-5-phosphoribosyl-1-pyrophosphate. Disproportionately high labeling of N-(3 + 9) was present in all four gouty subjects, most marked in the most flamboyant overproducers. The precursor glucine pool was sampled by periodic administration of benzoic acid and isolation of urinary hippuric acid. Similarly, the precursor glutamine pool was sampled by periodic administration of phenylacetic acid and isolation of the amide-N of urinary phenylacetylglutamine. The time course of (15)N enrichment of hippurate differed from that of the amide-N of glutamine. Whereas initial enrichment values of hippurate were very high, those of glutamine-amide-N were low, increasing to a maximum at about 3 h, and then declining less rapidly than those of hippurate. However, enrichment values of hippurate and of phenacetyl glutamine were normal in all of the gouty subjects studied. Thus, preferential enrichment of N-(3 + 9) in gouty overproducers given [(15)N]glycine does not necessarily reflect a specific abnormality of glutamine metabolism, but rather appears to be a kinetic phenomenon associated with accelerated purine biosynthesis per se.In addition, greater enrichment of N-9 than of N-3 on days 1 and 2 provided suggestive evidence for a second pathway for synthesis of the initial precursor of purine biosynthesis, phosphoribosylamine, perhaps utilizing ammonia rather than the amide-N of glutamine as nitrogen donor. In this limited study, the activity of this potential second pathway did not appear to be selectively increased in gout.
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PMID:The kinetics of intramolecular distribution of 15N in uric acid after administration of (15N) glycine. A reappraisal of the significance of preferential labeling of N-(3+9) of uric acid in primary gout. 435 99

Aseptic necrosis of the femoral head is a well-defined entity. The underlying diseases originate from very different types of pathological conditions. Alcoholism, cortisone therapy, gout or hyperuricemia, sickle cell anaemia and others all lead, through various pathways, to the impairment of the medullary blood flow. In many instances, a compartment syndrome can be demonstrated in the femoral head. Death of the osteocytes follows bone marrow necrosis. Revascularisation originates in the periphery of the necrotic segment. Vascular buds and fibroblasts invade the medullary space. New bone is laid over the necrotic trabeculae. Mechanical failure results from changes in the bony framework at three different levels. The subchondral boneplate may be weakened by the process of revascularisation, the necrotic trabeculae may fail because of diminished stiffness and strength, and overloading has been demonstrated at the junction between dead and living bone. Elevation of the intramedullary pressure is the first objective sign of impending or established bone necrosis. Scintigraphy with Technetium 99 m - Sulphur colloid can now show the early stages of marrow necrosis. Roentgenographic changes only appear in a later phase of the disease. Aseptic necrosis must be considered as involving both hips, unless proven otherwise. Attention given to the "silent hip" may allow salvage and prevent the occurrence of osteo-arthritic changes leaving merely unilateral disease. As long as the geometrical shape of the femoral head is maintained operation may well prove useful. The aim at this stage is to prevent collapse. It is impossible to know in the early stages whether mechanical failure will occur, but there is general agreement that the femoral head will eventually undergo deformation. A spherical epiphysis is therefore considered a success. All the conservative methods aim to decompress the medullary cavity. Core biopsy, curettage, bone grafting and intertrochanteric osteotomy all have their advocates. After fracture of the subchondral bone plate has occurred, there is evidence that grafts are unable to restore the strength of the necrotic area. Intertrochanteric osteotomy brings under the main load-bearing zone a vital part of the femoral head. Varus osteotomy can be successful if necrosis has spared sufficient of the lateral portion of the head. Rotation osteotomies, as proposed by Sugioka, are more radical and difficult operations. The published results are promising. Revascularisation of the weight-bearing area by pedicle grafts has been attempted, alone or in addition to osteotomy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Aseptic necrosis of the femoral head in young adults]. 638 8

An elevated level of blood uric acid (hyperuricemia) is the underlying cause of gout. Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Allopurinol, a widely used xanthine oxidase inhibitor is the most commonly used drug to treat gout. However, a small but significant portion of the population suffers from adverse effects of allopurinol that includes gastrointestinal upset, skin rashes and hypersensitivity reactions. Moreover, an elevated level of uric acid is considered as an independent risk factor for cardiovascular diseases. Therefore use of allopurinol-like drugs with minimum side effects is the ideal drug of choice against gout. In this study, we report the synthesis of a series of pyrimidin-5-one analogues as effective and a new class of xanthine oxidase inhibitors. All the synthesized pyrimidin-5-one analogues are characterized by spectroscopic techniques and elemental analysis. Four (6a, 6b, 6d and 6f) out of 20 synthesized molecules in this class showed good inhibition against three different sources of xanthine oxidase, which were more potent than allopurinol based on their respective IC(50) values. Molecular modeling and docking studies revealed that the molecule 6a has very good interactions with the Molybdenum-Oxygen-Sulfur (MOS) complex a key component in xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious, than allopurinol, to treat gout and possibly against cardiovascular diseases.
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PMID:Synthesis and xanthine oxidase inhibitory activity of 7-methyl-2-(phenoxymethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives. 2116 61