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We studied 14 patients (11 women and 3 men) from 18 to 33 years old, suffering from type I diabetes mellitus with normal renal function (creatinine clearance 106.91 +/- 28.73 ml/min) and serum uric acid below 2.5 mg/dl (2.34 +/- 0.11 mg/dl) as well as a high uric acid clearance (23.04 +/- 5.92 ml/min) and fractional urate excretion (21.4 +/- 2.6) versus urate clearance 9.82 ml/min and fractional urate excretion 8.80 +/- 1.3 in 14 normal control subjects. The study of the uricosuric mechanisms was conducted by the combination of probenecid (PB) test which inhibits the reabsorption of secreted urate, and pyrazinamide (PZA) test, which inhibits its tubular secretion. The results of studies indicate that the increase in urate clearance was accounted for by increased PZA-nonsuppressible urate suggesting a decreased reabsorption of filtered urate. Increased PZA-suppressible urate excretion combined with impaired response to a uricosuric drug is consistent with impaired reabsorption of secreted urate. According to our findings, increased urate excretion in diabetic patients may be attributed to the inhibition of both filtered and secreted reabsorption. This reabsorptive tubular abnormality is consistent with the view of an interference of tubular reabsorption of glucose with the tubular capacity for uric acid reabsorption.

The 2 subjects were a diabetic male with renal hypouricemia and a healthy male with normouricemia. In these subjects, 200 mg of benzbromarone increased fractional uric acid clearance (FUa) and 3.0 g of pyrazinamide decreased FUa. However, pyrazinamide did not inhibit the uricosuric action of benzbromarone at all on the administration of 3.0 g of pyrazinamide together with 200 mg of benzbromarone. These results indicated that in these cases, the relative role of each component could not be determined on the basis of the hypothetical four-component model.

The uricosuric properties of acetazolamide were investigated in order to elucidate the relationship between changes in proximal tubular sodium reabsorption and urate excretion in man. Acetazolamide produced a modest uricosuric response which was not suppressible by pyrazinamide. Alkalinization of the urine with sodium bicarbonate elicited an even smaller increment in the urate clearance. If urinary alkalinization does play a role in the uricosuric response to acetazolamide, it probably decreases urate reabsorption within the distal nephron. The present studies, when taken together with previous work, suggest that alterations in proximal tubular sodium and water reabsorption probably do not play an important role in the normal control of urate excretion or in the pathogenesis of hyperuricemic states. Diuretic-induced hyperuricemia occurring during extracellular fluid volume depletion probably results from either diminished tubular secretion of urate, accelerated postsecretory urate reabsorption, or both.

Acute and chronic studies were performed on 6 bealthy human volunteers. Four subjects took a Single oral dose of tienilic acid 1,000 mg. A week later, the same subjects took pyrazinamide (PZA) orally

Ticrynafen, 125--250 mg/day was compared with probenecid 0.5--1.0 g/day in patients with elevated serum uric acid values in a randomized, double-blind crossover study. Each treatment period lasted 12 weeks. The mean reduction in serum uric acid from 9.4 +/- 1.2 to 6.22 +/- 1.2 mg/dl (33.8%) during ticrynafen was greater (p less than 0.01) than that from 9.46 +/- 1.1 to 7.0 +/- 1.3 mg/dl (26%) during probenecid treatment. There were slight increases in serum creatinine and BUN and decreases in body weight during ticrynafen treatment. There were no statistically significant changes in serum electrolytes. The hypouricemic effect of ticrynafen was well maintained during its subsequent open-label administration for 18 months without any deterioration of renal function.

Tienilic acid (ticrynafen) [2,3-dichloro-4-(2-thyenil-carbonyl) phenoxyacetic acid] is a new diuretic with uricosuric properties in man and dog. In this animal the drug acts by blocking tubular transp

Studies employing pyrazinamide, which have included the measurements of clearances of pyrazinamide and pyrazinoate, as well as of ticrynafen itself and its principal metabolite, have lent support to the hypothesis that ticrynafen inhibits the tubular reabsorption of both filtered and secreted urate by nephrons of the human kidney. The inhibition of the reabsorption of secreted urate by ticrynafen appears to be quantitatively important for eliciting its uricosuric and hypouricemic responses. Because the uricosuric and natriuretic responses correlate with urinary ticrynafen concentrations, the drug appears to inhibit tubular reabsorption after gaining access to tubule fluid. As a consequence of its extensive binding to plasma proteins, clearance data suggest that tubular secretion of ticrynafen is necessary for its action.

We present 1 patient with hypouricemia and hyperuricosuria. Serum uric acid level ranged between 1.5 and 1.9 mg/dl and uric acid fractional excretion between 20 and 28%. Apart from that the renal function was normal. The pyrazinamide suppression test gave a normal response showing nearly complete suppression of urate excretion. The uricosuric response to sulfinpyrazone was normal too. The renal tubular response to extracellular fluid volume contraction induced by furosemide indicated a normal tubular sensitivity to extracellular fluid volume variations. From these results we conclude that our patient has a specific tubulopathy characterized by uric acid hypersecretion.

Studies were performed with ticrynafen (tienilic acid) to determine its natriuretic site of action, detailed electrolyte excretion, and its effect on acid excretion and bicarbonate reabsorption. With 500 and 1,000 mg oral doses under conditions of water diuresis, there was a decrease in free water excretion as osmolar clearance increased. During hydropenia, there was no change in free-water reabsorption as osmolar clearance increased. Maximum sodium excretion reached 5.2% of the filtered load. At 500 mg doses, there was no effect on phosphate excretion; with 1,000 mg doses, there was a reduction in phosphate excretion. During bicarbonate infusion, there was no change in the absolute or percent reabsorption of bicarbonate. After chronic administration of ticrynafen, there was no impairment of excretion of an acute acid load. Uric acid excretion increased at least threefold in all studies. The studies indicate that at 500 and 1,000 mg oral doses, ticrynafen has the characteristics of a diuretic which is active in the cortical diluting segment of the distal nephron.

Doses of 20, 40, 60 and 80 mg of the indanone diuretic MK-196 and 40 mg of frusemide were administered in random order to 5 healthy volunteers in a stable metabolic state, on the same day for 5 consecutive weeks. Diuresis, natriuresis and kaluresis increased with increasing doses, the natriuresis lasting for about 12 h and the kaluresis for about 24 h. Uricosuria increased with increasing doses of MK-196 and lasted for about 6 h. The uricosuria was followed by urate retention, so that there was little net change in the renal excretion of urate. Significant weight loss occurred, so that there was probably some associated plasma volume contraction, which would promote urate retention. By contrast, frusemide caused a reduction in renal excretion of urate at all times.