Uric Acid synthesis

Some drugs, such as the two-substituted thiodiazole and acetazolamide (Diamox), increase serum uric acid by stimulating uric acid synthesis (K9). Others, such as chlorothiazide (Diuril), increase uric acid retention by decreasing uric acid excretion (K9). Hydrochlorothiazide inhibits tubular secretion and has been shown to increase pretreatment mean uric acid values from 6.5 mg/100 ml to 10.3 mg/100 ml by the third treatment day. In a patient with gout, the level increased from 8 mg/100 ml to 12 mg/100 ml (H6). In a single case a paradoxical hypouricemia occurred (H6). 

Colchicine, an alkaloid obtained from the autumn crocus, has long been used and is relatively selective for the treatment of acute gouty arthritis. Unlike many of the newer agents for use in gout, colchicine has minimal effects on uric acid synthesis and excretion it decreases inflammation associated with this disorder. It is thought that colchicine somehow prevents the release of the chemotactic factors and/or inflammatory cytokines from the neutrophils, and this in turn decreases the attraction of more neutrophils into the affected area (Fig. 37.1).The ability of colchicine to bind to leukocyte microtubules in a reversible covalent complex and cause their depolymerization also may be a factor in decreasing the attraction of the motile leukocytes into the inflamed area. 

Allopurinol, in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption. This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine. 

A. Probenecid blocks active reabsorption of uric acid in the proximal tubules following glomerular filtration. It does not inhibit uric acid synthesis (B), stimulate tubular secretion (C), or inhibit the metabolism of purines (D). 

C. The dietary intake of purines is not a major contributing factor to uric acid blood levels. Therefore, pharmacological reduction of uric acid synthesis or increased excretion is required. Dietary restriction (A) can affect uric acid production if precursor molecules are lowered sufficiently, but this usually is not feasible. The question of drug specificity (B) is not germane to the question. Pathways of uric acid synthesis in the body (D) are well known. 

In a pathological condition that causes pain, drugs may be used either to care for the acute attack of pain or as prophylaxis to prevent the occurrence of pain. For example, colchicine is used during an acute attack of gout, and after the pain has subsided initially, the patient is switched to uricosuric agents such as probenecid or an inhibitor of uric acid synthesis such as allopurinol. 

One of the first studies that indicated the possible interference of ametbopterin and aminopterin with purine synthesis was the demonstration by Skipper et al. (S21) that administration of these compounds to mice inhibited the incorporation of labeled formate into nucleic acid purines. Ametbopterin (4-amino-A -methyl-pteroylglutamic acid) has produced some inhibition of uric acid synthesis during the use of this compound for treatment of leukemia (K15, E24). Another inhibitor of... 

Wl3. W3mgaarden, J. B., Seegmiller, J. E., Raster, L., and Blair, A. E., Utilization of hypoxanthine, adenine and 4-amino-5-imidazolecarboxamide for uric acid synthesis in man. Metab., Clin. ExpU. 8, 455-464 (1959). 

Currently, allopurinol is the only drug approved for use in inhibiting uric acid synthesis. Both allopurinol and its major metabolite, oxy-purinol, are xanthine oxidase inhibitors and thus impair the conversion of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol also lowers the intracellular concentration of PRPP. Because of the long half-life of its metabolite, allopurinol can be given once daily. An oral daily dose of 300 mg usually is sufficient. Occasionally, as much as 600 to 800 mg/day may be necessary. 

Gout is treated with diet and with several drugs. Dietary control (i.e., reduced consumption of food that is rich in nucleic acids such as liver and sardines) depresses uric acid synthesis in some individuals who are susceptible to primary gout. Allopurinol and colchicine are often used in gout therapy. Because allopurinol... 

N -Uric acid synthesis Amines from acylamines Ureas from amines... 

Phosphorus oxychloride has been used for the same purpose, but less often than the trichloride. Klosa699 has described a general process for using it in the preparation of carboxanilides. It was also used in preparation of (cyano-acetyl)urea as part of Traube s uric acid synthesis ... 

PRPP is an important intermediate in the de novo synthesis of purines pathway (Figure 22.4). Defects in PRPP synthetase may render it insensitive to feedback inhibition by purine nucleotides. Thus, purine nucleotides are overproduced, leading to excessive uric acid synthesis and gout (Figure 22.9). 

R. Behrend, O. Roosen, Liebigs Ante Chem. 251 (1888) 235 and 248 (the first uric acid synthesis starting from urea). 

Bien et al. (1953) studied one normal subject, and found an increase in renal uric acid excretion of 62 mg/day by nearly doubling the protein content of the diet. At the same time there was an increase in incorporation of N-glycine into uric acid, which was attributed to an increased endogenous uric acid synthesis. 

If there is an increased uric acid synthesis as well as an additional enhancement of renal excretion, one might expect constant serum levels of uric acid while excretion increases. In agreement with this hypothesis, there were publications which showed a considerable increase in renal excretion of uric acid and at the same time only slight or no variations in serum levels (Bowering et al., 1969). 

Firstly, the influence of main dietary representants, the carbohydrates, the fats, and the proteins on the acid—base balance should be mentioned. In addition, the function of the biosynthesized uric acid on the alkali reserve will be discussed in some detail. Subsequently, some quantitative aspects of uric acid synthesis, turnover, and renal and extrarenal excretion in healthy persons and gouty patients will be dealt with, followed by the detailed description of a special mechanism, preserving the serum bicarbonate by mobilization of bone phosphates. Finally, some clinical observations, supporting our concep- tion of the interrelation between hyperproduced uric acid and acid-base balance, will be discussed briefly. 

A more widely accepted scheme for uric acid synthesis was proposed in 1902 by Wiener. In this hypothesis urea was condensed with hydroxy-... 

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