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Advances in the management of gout: critical appraisal of febuxostat in the control of hyperuricemia.

Beara-Lasic L, Pillinger MH, Goldfarb DS - Int J Nephrol Renovasc Dis (2010)

Bottom Line: Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function.Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels.In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect.

View Article: PubMed Central - PubMed

Affiliation: Divisions of Nephrology, Department of Medicine, NYU Langone MedicalCenter, New York, NY, USA. lada.beara-lasic@va.gov

ABSTRACT
Gout recently passed rheumatoid arthritis to become the most common inflammatory arthritis in the United States (US). However, epidemiologic studies indicate that the quality of gout management is suboptimal owing to both patient and physician issues. Only three options for urate-lowering therapy are currently available in the US: allopurinol, probenecid, and recently, febuxostat. Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function. Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels. In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect. Febuxostat is a new medication that may offer several advantages and can be given as an alternative to allopurinol. We review the basic biology and clinical performance of febuxostat, and consider the potential utility of this agent in comparison to the older, better-established gout therapeutics.

No MeSH data available.


Related in: MedlinePlus

Chemical structure of febuxostat (Uloric® package insert; Takeda Pharmaceuticals America, Deerfield, IL).
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f1-ijnrd-3-001: Chemical structure of febuxostat (Uloric® package insert; Takeda Pharmaceuticals America, Deerfield, IL).

Mentions: Like allopurinol, febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid; Figure 1) inhibits xanthine oxidase (XO), an enzyme with a molybdenum-containing active site, to reduce the production of uric acid from hypoxanthine. Activity of XO depends on the redox state of its catalytic center molybdenum, complexed by a pterin compound to form the molybdenum-pterin cofactor. However, the mechanisms of action of these two XO inhibitors are not identical. Allopurinol is a purine analogue and is metabolized both by XO and by the phosphoribosyltransferases, hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and orotate phosphoribosyltransferase (OPRT), to form nucleotide analogues. Allopurinol exerts relatively weak competitive inhibition of the oxidized form of XO, which rapidly oxidizes allopurinol to oxypurinol. In turn, oxypurinol binds tightly to, and inhibits, the reduced form of XO, resulting in suicide inhibition of XO activity. In contrast, oxypurinol binds only weakly to the oxidized form of XO, and is displaced from the reduced form of the enzyme during spontaneous re-oxidation of molybdenum, with subsequent XO re-activation.


Advances in the management of gout: critical appraisal of febuxostat in the control of hyperuricemia.

Beara-Lasic L, Pillinger MH, Goldfarb DS - Int J Nephrol Renovasc Dis (2010)

Chemical structure of febuxostat (Uloric® package insert; Takeda Pharmaceuticals America, Deerfield, IL).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108781&req=5

f1-ijnrd-3-001: Chemical structure of febuxostat (Uloric® package insert; Takeda Pharmaceuticals America, Deerfield, IL).
Mentions: Like allopurinol, febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid; Figure 1) inhibits xanthine oxidase (XO), an enzyme with a molybdenum-containing active site, to reduce the production of uric acid from hypoxanthine. Activity of XO depends on the redox state of its catalytic center molybdenum, complexed by a pterin compound to form the molybdenum-pterin cofactor. However, the mechanisms of action of these two XO inhibitors are not identical. Allopurinol is a purine analogue and is metabolized both by XO and by the phosphoribosyltransferases, hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and orotate phosphoribosyltransferase (OPRT), to form nucleotide analogues. Allopurinol exerts relatively weak competitive inhibition of the oxidized form of XO, which rapidly oxidizes allopurinol to oxypurinol. In turn, oxypurinol binds tightly to, and inhibits, the reduced form of XO, resulting in suicide inhibition of XO activity. In contrast, oxypurinol binds only weakly to the oxidized form of XO, and is displaced from the reduced form of the enzyme during spontaneous re-oxidation of molybdenum, with subsequent XO re-activation.

Bottom Line: Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function.Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels.In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect.

View Article: PubMed Central - PubMed

Affiliation: Divisions of Nephrology, Department of Medicine, NYU Langone MedicalCenter, New York, NY, USA. lada.beara-lasic@va.gov

ABSTRACT
Gout recently passed rheumatoid arthritis to become the most common inflammatory arthritis in the United States (US). However, epidemiologic studies indicate that the quality of gout management is suboptimal owing to both patient and physician issues. Only three options for urate-lowering therapy are currently available in the US: allopurinol, probenecid, and recently, febuxostat. Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function. Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels. In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect. Febuxostat is a new medication that may offer several advantages and can be given as an alternative to allopurinol. We review the basic biology and clinical performance of febuxostat, and consider the potential utility of this agent in comparison to the older, better-established gout therapeutics.

No MeSH data available.


Related in: MedlinePlus