Abstract
Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.
Highlights
Gout is a crystal deposition disease with clinical manifestations that include acute gouty arthritis, chronic gouty arthropathy, tophi, and renal functional impairment due to monosodium urate (MSU) crystal deposition; and urolithiasis and obstructive uropathy due to uric acid crystal deposition [1]
Genetic, or disease-related excesses in urate production underlie hyperuricemia in some affected individuals [3], impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout [1,2,3]
Current urate-lowering options in allopurinol-hypersensitive gout patients who have had mild-to-moderate but not severe adverse reactions and who are not candidates for uricosuric therapy include: oral allopurinol desensitization, which is efficacious in about 50% of subjects [43]; and the use of oxypurinol
Summary
Gout is a crystal deposition disease with clinical manifestations that include acute gouty arthritis, chronic gouty arthropathy, tophi, and renal functional impairment due to monosodium urate (MSU) crystal deposition; and urolithiasis and obstructive uropathy due to uric acid crystal deposition [1]. The enzyme that catalyzes the terminal steps in urate production, namely oxidation of the purine bases hypoxanthine to xanthine and xanthine to uric acid, is a critical target of drug action in the treatment of hyperuricemia; this is discussed below. Agents that function through direct inhibition of xanthine oxidase activity include allopurinol and oxypurinol, which are hydroxypyrazolopyrimidine analogs of hypoxanthine and xanthine, respectively; and febuxostat, which is a thiazolecarboxylic acid derivative that is not a purine analog (Fig. 4). Current urate-lowering options in allopurinol-hypersensitive gout patients who have had mild-to-moderate but not severe adverse reactions and who are not candidates for uricosuric therapy include: oral allopurinol desensitization, which is efficacious in about 50% of subjects [43]; and the use of oxypurinol (the active metabolite of allopurinol; described below). It is likely that the therapeutic niches for modified uricases in the treatment of gout will be for short-term acceleration of tophus dissolution (‘debulking’) in carefully selected patients with large tophus burdens and perhaps for more long-term use in patients intolerant of or unresponsive to all other forms of urate-lowering therapy
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