Uric acid therapeutics

Although it might seem that adrninistration of enantiomericaHy pure substances would always be preferred, the diuretic indacrinone (3), is an example of a dmg for which one enantiomer mediates the harmful effects of the other enantiomer (4). (+)-Indacrinone, the diureticaHy active enantiomer or eutomer causes uric acid retention. Fortunately, the other enantiomer distomer) causes uric acid elimination. Thus, adrninistration of a mixture of the two enantiomers, although not necessarily racemic, may have therapeutic value. 

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

Uricostatic drugs inhibit the production of uric acid through the inhibition of xanthine oxidase. Allopurinol is the only therapeutically used uricostatic drug. 

Uricosuric dtugs increase the renal excretion of uric acid by inhibiting its renal reabsorption. Therapeutically used uricosuric dtugs are benzbromarone, probenecid and sulfinpyrazone. 

The therapeutic objective of antihyperuricemic therapy is to achieve and maintain a serum uric acid concentration less than 6 mg/dL, and preferably below 5 mg/dL. 

Pharmacology Thiazide diuretics increase the urinary excretion of sodium and chloride in approximately equivalent amounts. They inhibit reabsorption of sodium and chloride in the cortical thick ascending limb of the loop of Henie and the early distal tubules. Other common actions include Increased potassium and bicarbonate excretion, decreased calcium excretion and uric acid retention. At maximal therapeutic dosages all thiazides are approximately equal in diuretic efficacy. 

Mechanism of Action A xanthine oxidase inhibitor that decreases uric acid production by inhibiting xanthine oxidase, an enzyme. Therapeutic Effect Reduces uric acid concentrations in both serum and urine. 

Mechanism of Action An antigout agent that competitively inhibits reabsorption of uric acid at the proximal convoluted tubule. Also, inhibits renal tubular secretion of weak organic acids, such as penicillins. Therapeutic Effect Promotes uric acid excretion, reduces serum uric acid level, and increases plasma levels of penicillins and cephalosporins. 

Mechanism of Action A uricosuric that increases urinary excretion of uric acid, thereby decreasing blood urate levels. Therapeutic Effect Promotes uric acid excretion and reduces serum uric acid levels. 

The tubular secretion of penicillin is inhibited by probenecid, so that the blood concentration and its half life (therapeutic effects) is prolonged with the simultaneous use of these two drugs. Phenylbutazone can block the renal tubular reabsorption of uric acid, leading to uricosuria. 

Theophylline is 1,3-dimethylxanthine theobromine is 3,7-dimethylxanthine and caffeine is 1,3,7-trimethylxanthine. A theophylline preparation commonly used for therapeutic purposes is aminophylline, a theophylline-ethylenediamine complex. The clinical use of theophylline is discussed below. The metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine. 

Inosine pranobex is a synthetic product, also known as isoprinosine or inosine dimepranol acedobene, with antiviral properties that are assumed to be related to its effect on T cell-mediated immunity rather than to direct antiviral activity. It has been tried in a wide range of viral diseases and also in rheumatoid arthritis (1), multiple sclerosis (2), and alopecia (3). However, clinical trials have mostly shown only modest therapeutic benefit or none at all (1,4), and no specific adverse effects, except for an increase in serum uric acid concentrations (5), reflecting the metabolic pathways of purines (6). 

Reduced plasma triglycerides, increased S-hydro-xybutyrate, and increased plasma uric acid were noted over 6 days of administration of DCA as a hypoglycemic agent. Although there is no conclusive evidence, DCA is proposed to cause neurotoxic effects in humans based on the fact that DCA inhibits its own metabolism. These effects are expected to occur at therapeutic doses, 25-100 mg kg... 

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