What is 'Gout'?
|
||||||
Incidence of Gout Gout is a disease
characterized biochemioully by hyperuricernia and clinically by episodes of severe, acute
arthritis. When not treated, it passes through four stages: asymptomatic
hyperuricemia,
acute gouty arthritis, intercritical (interval) period, and chronic tophaceous gout. Hyperuricemia may be (a)
primary, when it results from a metabolic error that leads to an overproduction and/or
decreased clearance of uric acid; or (b) secondary, when it is a consequence of
another disease or of drug therapy1. (1) About 0.7% of men and 0.1% of women in the US. develop gout. (2) and about 2 million Americans have this disorder. Definition
of Gout
Gout is a metabolic disease in which increased levels of uric acid in the blood become deposited within joints and tissues. The major cause of gout is the ineffective metabolism of a nucleic acid in the body called purine. The normal metabolism of purine results in an endproduct called uric acid, which then gets exereted by the kidneys. In gout, however, metabolic problems cause uric acid to be overproduced and/or underexcreted. In about 90% of cases, gout is due to the underexcretion of uric acid from the kidneys. When uric acid builds up in the blood, it causes the formation of needle-like crystals (called urate crystals) which irritate the joint lining and cause severe joint inflammation, or an acute gout attack. The urate crystals also may form a deposit in the joint (called a tophus). In about 3 out 4 people with gout, the big toe joint is affected, but any joint may be involved including the knees, ankles, fingers, wrists, or elbows. Women, in particular, are likely to experience gout in the hands. Another possible result of high blood uric acid levels is the development of kidney stones. |
History of Gout |
|---|
It is very likely that one of
the first useful drugs in gout was an extract from the plant Colchicum autumnale. Preparations
from this plant have been used since the sixth century. Colchicum was known as hermodactyl
(finger of Hermes) and articulorum (soul of the joints), because of its effect
in the relief of pain of articular origin. In 1763, von Storck introduced it for the
treatment of acute gout. In 1820, Pelletier and Caventou isolated from the plant the
alkaloid colchicine. Its chemical structure was determined by Dewar in 1945. Its total
synthesis was performed independently by Eschenmoser and van Tamelen and co-workers in Clinical studies with
anti-inflammatory drugs, such as adrenal corticosteroids, corticotro‚pin,
3,5-pyrazolidinediones, and arylalkanoic acids, led to their introduction in the therapy
of acute gouty arthritis.
Probenecid was first synthesized
by Miller in 1950 and evaluated by Beyer et al. that same “ear.
Structuraly,
it is related to carinamide, a compound with uricosuric activity and then uscd to increase
penicillin blood levels. Probenecid was therefore designed as a potential depressor of
renal tubular excretion of penicillin blood levels. Probenecid was therefore designed as a
potential depressor of renal tubular excretion of penicillin at a time when this
antibiotic was scarce.
Allopurinol is a product of
rational drug design. From 1942on, Hitchings, Elion,and co‚workers, in an effort to introduce new antineoplastic
agents, started to synthesize and evaluate potential antimctabolites of the purine and
pyrimidine bases of the nucleic acids. Allopurinol was designed to be an inhibitor of xanthine
oxidase, the enzyme that catalyzes the biosynthesis of uric acid (Figure 18.4). Tried
first in leukemie patients, it produced a marked decrease in
plasma and urinary levels of uric acid. This effect suggested its potential usefulness in
the therapy of primary gout. In 1963, Rundles and co-workers performed, with great
success, the first clinical trial of allopurinol in gout. Later it was seen that its metabolite, oxypurinol, is equally
active1.
|
|
|
