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Objectives
Review the clinical features of gout Review the rationale for therapies of gouty arthritis and the underlying hyperuricemia Answer questions
Stage I
Asymptomatic Hyperuricemia Serum Urate > 7.0 mg/dl
Prevalence of Hyperuricemia
Adult Males U.S. France Hospitalized Males Los Angeles VA Milwaukee VA 5% 17%
13% 21%
Determine the cause Address contributing factors Hypertension Obesity Alcoholism Hyperlipidemia At this time, specific urate-lowering drugs are not indicated
Stage II
Acute Gouty Arthritis Intercritical Gout
Colchicine inhibits E-selectin mediated PMN adhesion PMN L-selectin expression Il-1 expression Il-8 production PMN motility Chemotaxis
NSAIDs Inhibits PGE2 Corticosteroids Inhibit PGE2 and LTB4 Stabilize lysosomal membranes ACTH Agonist of the leukocyte melatonin receptor-3
The secret is not what is used, but how quickly therapy is initiated after the attack begins!
Stage III
Antihyperuricemic Therapy
1. 2. 3. 4. Treat acute attack until resolved Colchicine or NSAID for prophylaxis Xanthine oxidase inhibitor or uricosuric Address other problems Hypertension Obesity Alcoholism
Serum Urate 5.0 mg/dl! Lowering serum urate to > 7.0 mg/dl does not reverse the problem. It only slows the rate of progression.
Compliant patients Under 60 years old Good renal function* No ASA Can use 81 mg but sould be taken 6 hours after the uricosuric No history of kidney stones Underexcrete uric acid
Everyone except those Sensitive to it Taking azathioprine Allopurinol has Once-a-day dosage Few drug-drug interactions Effective in renal failure* Can be used in overproducers and underproducers
Although there have been no new urate-lowering therapies available to treat gout since 1964, there will be soon.
Febuxostat
Puricase
III
II
NP-SIXO
PEG urate oxidase
Uricase PEG20
oxypurinol
I
II
Y-700
KT-433
I-II
II
XOI
Uricosuric
Febuxostat
A nonpurine, selective inhibitor of xanthine oxidase in phase III studies for the treatment of hyperuricemia in patients with gout
OH CH3 O N N H3C
N
NC S CH3
N H
Allopurinol
Febuxostat
CO2H
Potent inhibition with significant urate reduction Ability to administer in renal insufficiency1 and mild or moderate hepatic insufficiency with no dosage adjustments2
Safe, effective and well tolerated in limited data of allopurinol intolerant patients3 1. Swan et al. Arthritis Rheum. 2003;48(9):S529.
2. Khosravan et al. Arthritis Rheum. 2004;50(9):S806. 3. Becker et al. Arthritis Rheum. 2004;50(9):S803.
Study design: randomized, double-blind, 52 week, multicenter trial. Objective: to assess safety and efficacy (vs. allopurinol) of daily febuxostat administration in lowering sUA levels in subjects with gout and hyperuricemia (sUA 8.0 mg/dL). Enrollment: N=760 subjects
Compared to allopurinol, significantly more patients on either dose of febuxostat were able to achieve mean serum urate concentrations less than 6.0 mg/dL
Proportion of Subjects with sUA <6.0 mg/dL (ITT Subjects) Febuxostat 80 mg Last 3 sUA <6.0 mg/dL 53% (136/255)* Febuxostat 120 mg 62% (154/250)* 82% (119/145)* Allopurinol 300 mg 21% (53/251) 39% (70/178)
Treatment Failures
Poor prescription Poor compliance