Irving H. Fox

Renal excretion of uric acid during prolonged fasting

Serum and urine uric acid were evaluated during prolonged therapeutic fasting in 15 obese patients. With increasing ketonemia the serum uric acid rose from a control value of 5.9 +/- 0.4 to 12.5 +/- 1.0 mg/100 ml at 7 days and then decreased progressively to 7.7 +/- 1.3 mg/100 ml by 28 days despite sustained ketonemia. The uric acid clearance were 5.5 +/- 0.9, 1.8 +/- 0.2, and 4.4 +/- 1.5 ml/min at days 0, 7, and 25 of fasting. At the same times the creatinine clearances were 114 +/- 11, 80 +/- 6, and 64 +/- 6.3 ml/min. There was no evidence of a renal tubular abnormality as assessed by glycosuria, bicarbonaturia, or increased phosphaturia. Urate binding to plasma proteins remained unchanged. Acute studies of the renal handling of uric acid revealed a uricosuric response to the administration of sodium lactate or sodium bicarbonate by intravenous infusion and low-dose acetylsalicylic acid orally. This renal tubular response departs significantly from that observed during the overnight fasted state and could not be accounted for by extracellular fluid volume expansion or the induced acid-base changes.

Inhibition of Mitogen Mediated Lymphocyte Blastogenesis by Adenosine

The effect of adenosine on the proliferative response of human peripheral circulating lymphocytes to stimulation by concanavalin A, phytohemagglutinin and pokeweed mitogen was evaluated. Increasing concentrations of adenosine substantially inhibited mitogen mediated lymphocyte blastogenesis. Erythro-9(2-hydroxyl-3-nonyl) adenine. HCl enhanced the inhibitory effect of adenosine. Inosine, the deamination product of adenosine, had an inhibitory effect which was less than that of adenosine. Inhibition by adenosine may be relevant to the normal regulation of immune function and may account in part for the pathophysiological relationship between severe combined immunodeficiency disease and adenosine deaminase deficiency.

Purine Ribonucleotide Catabolism: Clinical and Biochemical Significance

Purine ribonucleotides are degraded to uric acid by a complexly regulated metabolic pathway. Abrupt lowering of intracellular ATP, a physiological inhibitor of this pathway at normal concentrations, p

Mechanism for the Paradoxical Aciduria Following Alkali Administration to Prolonged-fasted Patients

Rapidly induced systemic alkalinization due to either sodium-lactate or sodium-bicarbonate infusion in prolonged-fasted subjects with steady-state ketoacidosis was associated with a decrease in urine pH. This decrease in urine pH from 5.50 to 5.20 was the result of a significant decrease in urinary ammonium excretion from 8.40 to 6.35 mEg/hr and was not accompanied by an increase in net acid excretion (11.3 vs. 10.6 mEg/hr). The decreased ammonium excretion is attributed to the raised pH of the proximal tubular fluid resulting in a less favorable pH gradient for gaseous ammonia entry. This would decrease gaseous ammonia generated in the loop of Henle for collecting duct buffering of secreted hydrogen ions.

The Pharmacology of the Hypouricemic Effect of Benzbromarone

The hypouricemic effect of benzbromarone has been investigated in six subjects. Benzbromarone increased urate: creatinine by 371 per cent over control values at two to four hours after administration. Over a 24 hour period, the mean serum uric acid decreased from a control value of 7.8 +/- 0.8 to 4.3 +/- 0.6 mg/dl. This uricosuric effect was completely reversed by pyrazinamide, partially inhibited by acetylsalicyclic acid and sulfinpyrazone, and was not accompanied by an elevation of the creatinine clearance or an inhibition of urate binding to plasma protein. In vitro studies showed only 22 per cent inhibition of urate binding by benzbromarone five muM, a concentration which is transiently reached in man. Kinetic studies of human liver xanthine oxidase demonstrated non-competitive inhibition with variable hypoxanthine and a Ki slope of 8.5 muM. The Ki slopes for benzarone and allopurinol were 19.0 muM and 0.05 muM respectively. There was no elevation of the urinary oxypurines following benzbromarone ingestion. These observations suggest that only the renal tubular activity of benzbromarone is relevant to its hypouricemic effects in man. (J Rheumatol 2: 437-445, 1975).

Hypoxanthine-guanine phosphoribosyltransferase: Mosaicism in the peripheral erythrocytes of a heterozygote for a normal and a mutant enzyme

A mutant form of erythrocyte hypoxanthine-guanine phosphoribosyltransferase with an abnormal isoenzyme pattern was found in a patient with a partial enzyme deficiency and X-linked gout. This abnormal pattern was a marker for the mutant enzyme in hemolysate from the heterozygote for the enzyme deficiency.

Acquired increases of human erythrocyte purine enzymes

The alterations of three erythrocyte purine enzymes were studied in 12 patients with diseases associated with reticulocytosis, two patients with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, seven patients with severe megaloblastic anemia, and 14 normal subjects. The specific activity of adenine phosphoribosyltransferase was positively correlated (r = 0.81) with the reticulocyte percentate in ten patients with a normal hypoxanthine-guanine phosphoribosyltransferase. Two apparent types of alterations of this enzyme were distinguished: (1) increased specific activity with a normal half life as in megaloblastic anemia, and (2) a prolonged half life with or without an elevation of specific activity as in the deficiency of hypoxanthine-guanine phosphoribosyltransferase. Hypoxanthine-guanine phosphoribosyltransferase and phosphoribosylpyrophosphate synthetase were increased in megaloblastic anemia, but were not correlated with the reticulocyte percentage and did not have a consistent change in the half life in the other disorders studied. The data show that acquired disorders associated with reticulocytosis may cause an elevation of the specific activity of purine enzymes in peripheral circulating erythrocytes. Therefore, these factors must be carefully considered in the interpretation of an elevated level of enzyme activity.

Effects of vitamins on the renal handling of uric acid.

The use of vitamins in megadoses has been popular in our modern society for the treatment of many problems. Although these compounds are often of dubious therapeutic value except for the specific management of vitamin deficiency, it has often been assumed that they are innocous in a large dose. Diseases associated with the excessive ingestion of certain vitamins are well known and new adverse effects are continually being described.

Alterations of human purine metabolism in megaloblastic anemia.

Secondary hyperuricemias in hematological diseases are frequently related to an increased turnover of nucleic acid purine in rapidly proliferating cells or in hyperplastic tissue (1). Transient hyperuricemia, hyperuricosuria and acute gouty arthritis have occurred during liver extract induced reticulocytosis and during the therapy for deficiencies of folic acid or iron (1–4). To further explore the acute alterations of purine metabolism, we have investigated 7 patients with severe megaloblastic anemia for changes of uric acid metabolism and 3 important erythrocyte enzymes of purine metabolism (5).

Phosphoribosylpyrophosphate synthesis in human erythrocytes: inhibition by purine nucleosides.

The intracellular concentration of PP-ribose-P is a balance between its formation and its utilization. Purine nucleosides stimulate PP-ribose-P formation in mammalian cells when inorganic phosphate exceeds 20 mM (1,2). This occurs by the conversion to ribose-5-phosphate of the ribose-1-phosphate liberated from nucleosides by purine nucleoside phosphorylase. Recently Bagnara and Finch (3) showed that nucleosides decreased intracellular PP-ribose-P in Escherichia coli incubated in 1.4 mM inorganic phosphate. The reason for the latter effect has not been clear since there is no substantial direct effect of nucleosides on purified PP-ribose-P synthetase.