Gout

Gout results from the deposition of urate crystals (monosodium urate monohydrate) in joints, leading to an acute inflammatory response, or in soft tissues, such as cartilage, causing no inflammation. Most cases of gout are characterized by the sudden onset of severe acute monarticular arthritis in a peripheral joint in the leg. 

Three treatments are available for patients with acute gouty arthritis. Colchicine is less favored now than in the past because its onset of action is slow and it invariably causes diarrhea. Nonsteroidal antiinflammatory drugs, which are currently favored, are rapidly effective but may have serious side effects. Corticosteroids, administered either intraarticularly or parenterally, are used increasingly in patients with monarticular gout, especially if oral drug therapy is not feasible. 

Drugs used in the management of gout are To treat acute gouty arthritis 

FIGURE 57 Cyproterone inhibits tiie action of androgens, and gossypol 

Indications Adults— used for prevention of chemotherapy-induced nausea and vomiting prevention of radiation-induced nausea and vomiting (oral only) postoperative nausea and vomiting (injection only). Pediatric (2 to 16 years)— used for prevention of chemotherapy-induced nausea and vomiting (injection only). Safety and efficacy are not established in patients younger than 2 years. 

The therapy of gout is twofold (1) treatment of the acute attack and (2) chronic lowering of hyperuricemia. 

Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms 

Chronic lowering of urate levels below 6 mg/1 blood requires (a) an appropriate diet that avoids purine (cell nuclei )-rich foods (e.g., organ offal) and (b) urico-statics for decreasing uric acid production. 

Allopurinoi, as well as its accumulating metabolite, oxypurinol ( alloxanthine ), inhibits xanthine oxidase, which catalyzes urate formation from hypoxanthine via xanthine. These precursors are readily eliminated via the urine. Allopurinoi is given orally (300-800 mg/day). Apart from infrequent allergic reactions, it is well tolerated and is the drug of choice for gout prophylaxis. Gout attacks may occur at the start of therapy but they can be prevented by concurrent administration of colchicine (0.5-1.5 mg/day). 

Uricosurics, such as probenecid or benz-bromarone (100 mg/day), promote renal excretion of uric acid. They saturate the organic acid transport system in the proximal renal tubules, making it unavailable for urate reabsorption. When underdosed, they inhibit only the acid secretory system, which has a smaller transport capacity. Urate elimination is then inhibited and a gout attack is possible. In patients with urate stones in the urinary tract, uricosurics are contraindicated. 

Several disorders affect purine metabolism. They are gout and the syndromes associated with deficiency of HPRT, APRT, adenosine deaminase, nucleoside phosphorylase, myoadenylate deaminase, and xanthine oxidase. 

Structures of tautomeric forms of uric acid. In the lactim form, uric acid has two acidic hydrogens, with pK values of 5.75 and 10.3. At physiological pH (7.4), the predominant species of the lactim form is urate monoanion. 

Primary gout is a disorder of purine metabolism seen predominantly in men. The condition is multifactorial and involves genetic and nongenetic factors. Occurrence in women is uncommon when it does occur, it is usually found in postmenopausal women. The blood urate concentration of normal men is 1 mg/dL higher than that in women, but this difference disappears after the menopause. Thus, in women, the postmenopausal rise in serum urate levels may increase the risk of developing gout. Gout is very rare in children and adolescents. 

Secondary gout develops as a complication of hyperuricemia caused by another disorder (e.g., leukemia, chronic nephritis, polycythemia). This type of hyperuricemia usually is associated with abnormally rapid turnover of nucleic acids. The rare cases of gout in adolescents and children are usually of this type. 

Nonsteroidal anti-inflammatory drugs, such as indomethacin and phenylbutazone, are also effective. In severe cases, glucocorticoids may be indicated. 

Effective prophylaxis of gout attacks requires urate blood levels to be lowered to less than 6 mg/100 mL. 

Purine (cell nuclei)-rich foods should be avoided, e.g., organ meats. Milk, dairy products, and eggs are low in purines and are recommended. Coffee and tea are permitted since the meth-ylxanthine caffeine does not enter purine metabolism. 

Non-steroidal anti-inflammatory drugs (NSAIDs) Ibuprofen, celecoxib 

Drugs that suppress the rheumatic Gold salts, penicillamine, 

Cytokine inhibitors Etanercept, infliximab, adalimumab, anakinra 

Institute for Health and Clinical Excellence (NICE) guidelines currently recommend it is only used in controlled long-term clinical studies. 

Rituximab is a monoclonal antibody that destroys B lymphocytes. It was previously licensed only for the treatment of particular types of leukaemia (see Chapter 10). Since November 2006, rituximab has been licensed for treatment of refractory rheumatoid arthritis, where other treatments, including anti TNF-a have failed to produce an adequate response. NICE guidelines were produced in 2007. 

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Puel J.P. (1987) Some results on optimal control for unilateral problems. Gout. Partial Diff. Equat. Lect. Notes in Control and Infor. Sci. 114, Springer-Verlag, 225-235. 

Nucleic acid contents of SCP products, which range up to 16% in bacteria and 6—11% in yeasts, must be reduced by processing so that intakes are less than 2 g/d to prevent kidney stone formation or gout. Adverse skin and gastrointestinal reactions have also been encountered as a result of human consumption of some SCP products (87). 

Deficiency or Toxicity in Humans. Molybdenum deficiency in humans results in deranged metaboHsm of sulfur and purines and symptoms of mental disturbances (130). Toxic levels produce elevated uric acid in blood, gout, anemia, and growth depression. Faulty utiH2ation results in sulfite oxidase deficiency, a lethal inborn error. 

Information on the toxic effects of molybdenum in humans is scarce. A high incidence of gout was reported in a locale in Armenia where the soil contained exceptionally high levels of both molybdenum and copper (15). However, the significance of the suggested correlation is questionable because of the lack of information on the study population and the absence of a control group. 

Colchiciae (23) is a toxic substance occurring ia Colchicum autumnale, it coataias the aucleus of pyrogaUol trimethyl ether. Colchiciae has beea used ia the treatmeat of acute gout, and ia plant genetics research to effect doubling of chromosomes. 

The presence of nucleic acids ia yeast is oae of the maia problems with their use ia human foods. Other animals metabolize uric acid to aHantoia, which is excreted ia the uriae. Purines iagested by humans and some other primates are metabolized to uric acid, which may precipitate out ia tissue to cause gout (37). The daily human diet should contain no more than about 2 g of nucleic acid, which limits yeast iatake to a maximum of 20 g. Thus, the use of higher concentrations of yeast proteia ia human food requires removal of the nucleic acids. Unfortunately, yields of proteia from extracts treated as described are low, and the cost of the proteia may more than double. 

The active principle of the autumn crocus (Colchicum autumnale), colchicine (48), is one of the very few drugs that have remained in reputable medical use since ancient times. This drug was the only useful treatment available for the excruciating pain associated with crystallization of uric acid in the joints characteristic of gout until the advent of allopurinol. Although the precise mechanism by which colchicine gives this dramatic relief remains undefined, the antimitotic activity of this agent is... 

Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-... 

As an inhibitor of xanthine oxidase, allopurinol also markedly decreases oxidation of both hypoxanthine and xanthine itself to the sole source of uric acid (19) in man. This metabolic block thus removes the source of uric acid that in gout causes the painful crystalline deposits in the joints. It is of interest that allopurinol itself is oxidized to the somewhat less effective drug, oxypurinol (21), by xanthine oxidase. 

Gicht, /. top, mouth, throat (of a furnace or crucible) charge (for a furnace) (Med.) gout. 

Gicht gas, n. gas from the top of a blast furnace, blast-furnace gas top gas, exit gas, mittel, n. remedy for gout. rauch, m. top smoke (of a blast furnace). -rose, /. peony, rhododendron, -riibe,/. bryony, -schwamm, m. incrustation near a furnace top (Zinc) tutty. staub, m. blast-furnace dust flue dust. 

Therapeutic Function Xanthine oxidase inhibitor gout therapy Chemical Name 1 H-pyra2olo[3,4-d] pyrimidin4-ol Common Name —... 

Uric acid, HCs C N can accumulate in the joints. This accumulation causes severe pain and the condition is called gout Ka for uric acid is 5.1 X 10-6. For a 0.894M solution of uric acid, calculate... 

A painful arthritic condition known as gout is caused by an excess of uric acid HUric in the blood. An aqueous solution contains 4.00 g of uric acid. A 0.730 M solution of KOH is used for titration. After 12.00 mL of... 

Anti-gout Drugs. Figure 1 Xanthine oxidase-catalyzed reactions. Xanthine oxidase converts hypoxanthine to xanthine and xanthine to uric acid, respectively. Hypoxanthine and xanthine are more soluble than uric acid. Xanthine oxidase also converts the uricostatic drug allopurinol to alloxanthine. Allopurinol and hypoxanthine are isomers that differ from each other in the substitution of positions 7 and 8 of the purine ring system. Although allopurinol is converted to alloxanthine by xanthine oxidase, allopurinol is also a xanthine oxidase inhibitor. Specifically, at low concentrations, allopurinol acts as a competitive inhibitor, and at high concentrations it acts as a noncompetitive inhibitor. Alloxanthine is a noncompetitive xanthine oxidase inhibitor. XOD xanthine oxidase. 

Anti-gout Drugs. Figure 2 Reabsorption and secretion of uric acid in the proximal renal tubulus. (a) Normal situation. Uric acid is completely reabsorbed in the proximal segment of the renal tubulus and secreted more distally. (b) Situation in untreated hyperuricemia. 

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