A method for determining uric acid clearance to evaluate uricosuric drugs was planned with urate oxidase inhibitor-treated rats. The metabolism of uric acid to allantoin in the animals was inhibited by administration of potassium oxonate 250 mg/kg i. p. twice with a 2-hour interval. Five 20-minute clearance experiments on uric acid and inulin were successively done from 40 minutes after the second administration of potassium oxonate und er anesthesia with urethane. Test drugs were given i. p. just after the first urine collection. Under the experimental conditions, th e animals showed well-controlled levels of urine volume, urineexcreted amount of uric acid, plasma uric acid, inulin clearance and uric acid clearance, and the fractional excretion of uric acid was nearly 0.6. The free-type ratio of plasma uric acid in the animals was 97%, and hence the fractional excretion supported the reabsorptive net flux of uric acid in the tubules. Uricosuric agents, probenecid and tienilic acid increased the urine-excreted amount of uric acid with an obvious elevation o f fractional excretion of uric acid. A high dose of furosemide, which had been reported to inhibit the tubular secretion of uric acid, decreased the fractional excretion of uric acid with a rise of plasma uric acid. Thiazide diuretics such as trichloromethiazide and hydrochlorothiazide also increased the urine-excreted amount of uric acid together with increases of urine volume and fractional excretion of uric acid. These-results agree well with the characteristics of the drugs used. No practical procedure has been available for evaluating uricosuric drugs by animal experiments, except for those using primates such as chimpanzees and cebus monkeys, because of species differences in the metabolism and excretion of uric acid. Thus, the method proposed here with a commonly used animal is very practical and useful. However, although the cause is not clear, uricosuric drugs such as probenecid and tienilic acid obviously increased plasma uric acid during the clearance experiment. This was an unexpected effect from the clinical view point of the drugs and needs to be studied further.
The synovial fluid from patients with gouty arthritis showed an enhanced activity to induce superoxide generation by neutrophils and decreased complement levels, as compared to synovial fluid of osteoarthritis. Allopurinol inhibited superoxide generation by hypoxanthinexanthine oxidase system (HPX-XOD) in dose dependent fashion. Colchicine in extremely higher dose than clinically used inhibited superoxide generation both by HPX-XOD and neutrophils. The role of urate crystals in the synovia l fluid on superoxide generation and complement activation was discussed.
Three hundred mg of sobrerol were administered daily to 9patients with gout for 2 weeks, and serum urate level (Sua), urinary excretion of urate (Uua) and uric acid clearance (Cua)were determined before and after the sobrerol administration. Sua before and after the administration were 9.9 and 7.7 mg/dl, respectively, Uua were 0.54 and 0.35 mg/kg/hr, respectively, and Cua were 5.1 and 6.4 ml/min, respectively. These findings suggest that sobrerol reduced serum urate level by inhibiting urate production in gouty subjects. Sobrerol reduced significantly IMP contents in acid soluble fraction, but the agent did not inhibit hypoxanthine 14C incorporation into acid insoluble fraction of L1210 cells incubated in the presence of sobrerol, suggesting that the agent inhibited purine de novo syn thesis of the cells. Unlike allopurinol, sobrerol did not inhibit xanthine oxidase activity.
Three children with urinary stones were referred to us for evaluation of adenine phosphoribosyltransferase(APRT) activity in red blood cells(RBCs), mononuclear cells(MNCs), and polymorphonuclear cells(PMNLs). They had no APRT activity in their RBCs, MNCs, and PMNLs. They were the third, forth, and fifth cases with complete deficiency of this enzyme in Japan. In their five asymptomatic relatives, the RBC-APRT activity was more than two standard deviations(SD) below the mean for controls, indicating they seemed to be heterozygotes. The PMNLAPRT activity in heterozygotes was more than one SD below the mean for controls, but the MNC-APRT activity was within the normal range, because of the wide variation of normal values. The determination of MNC- or PMNL-APRT activity can show homozygosity in this disorder, but it may be impossible to distinguish heterozygotes from normal subjects. The measurement of RBC-APRT activity seems to be useful in diagnosing both homozygotes and heterozygotes of APRT dificiency.
Eleven years follow up observation has been done in an adult patient with glycogen storage disease type 1 with special reference to the serum uric acid. In 1969 at the first visit to our hospital, he was 20 years old and his serum uric acid was 13.5 mg/dl. Serum uric acid was controlled under 8 mg/dl by administration of benzbromarone or allopurinol. As he felt well he stopped to take any drug since December 1971. Nevertheless his serum uric acid remained at 9.8mg/dl in January 1977 and it was rather lowered to 7.7 mg/dl in October 1980. Laboratory data in 1969 and 1980 showed that lipid metabolism was improved but glucose was not. Although the real reason is not clear, the partial deficiency of enzyme, or an adaptation of metabolism was considered for the spontaneous improvement of uric acid metabolism in this case.
The uric acid level, carcinoembryonic antigen (CEA) and lactic dehydrogenase (LDH) in serum and ascites were determined in 11benign diseases and 18 malignant diseases with ascites. The results obtained were as follows.1) 91 per cent of 11 benign diseases showed higher uric acid levels in serum than in ascites. On the other hand,89 per cent of 18 malignant diseases showed higher uric acid levels in ascites than in serum. Uric acid levels below 6.0 mg/dl in both serum and ascites were almost totally in benign diseases. Uric acid levels above 8.0 mg/dl in both serum and ascites were supposed to be malignant.2) Concerning the CEA levels,100 per cent of benign diseases showed higher level in serum than in ascites. On the other hand,61 per cent of 18 malignant diseases showed higher level in ascites than in serum. Both liver cirrhosis and hepatic cancer were higher CEA level in serum than in ascites, and so differential diagnosis was difficult by means of the measurement of CEA levels in serum and ascites.3) Concerning the LDH levels,100 per cent of benign diseases showed higher level in serum than in ascites. On the other hand,22 per cent of malignant diseases showed higher level in ascites than in serum. The above results suggest that the measurement of uric acid levels in both serum and ascites was very useful in order to make the differential diagnosis of benign and malignant diseases with ascites.
We examined hypouricemia in admitted patients (31 cases) and obtained the following conclusion. 1) In all cases, hypouricemia was transient. 2) Hypouricemia associated with liver disease was found in 21cases among 31 cases (68%) and liver dysfunction was relative mild. 3) We observed the clinical course of the alternation of liver function test and uric acid concentration in course of time. Hypouricemia in one group appeared in the same time of the worse change of liver function, and hypouricemia in the other group appeared after the worse change of liver function. 4) In one case of hypouricemia, serum and urine oxypurine concentration increased as liver function became worse. It is suggested that hypouricemia may be affected by xanthine oxidase.