Change of uric acid in the course of their cataract development induced by galactose was investigated. Uric acid in rat lenses was quantitatively determined by high-performance liquid chromatography with electrochemical detection. We found that the amounts of uric acid in creased in the rat lenses with the development of their opacification induced by galactose compared with the control group. The observed increase of uric acid in the galactose-induced cataractous lenses might be interpleted as follows. (1) Adenosine 5'-triphosphate might consumed in the course of the cataract development and/or the salvage system in the purine metabolism might be relatively deactivated. As a result, the synthesis of uric acid might be also enhanced. (2) After the initial membrane-permeability change induced by plausible polyol accumulation in rat lens, uric acid might be able to transfer from the extr a - l ens into the intra-lens through the lenticular membrane. At this moment, however, we have been unable to obtain any direct evidence for the above described assumptions.

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We examined the effect of diltiazem on rat hearts using the Langendorff method. Perfusion was stopped during the ischemia to distinguish the effect of duration without the flow from that with reperfusion. Recovery of the myocardial function from ischemia/reperfusion in the control experiment was about 20% without recovery of the decreased ATP level in the myocardium. In contrast, diltiazem treatment prior to the ischemia led to recovery of the cardiac function after the reperfusion, although it had no effect on the reduction of the myocardial ATP level just after the ischemia; the ATP level recovered after the reperfusion. Diltiazem treatment also enhanced uric acid production in the reperfusion from the purine catabolites, which had been pooled in the myocardium during the ischemia. These results showed that uric acid production can occur in heart preparations and is not always related to the development of myocardial injury. We concluded that the protective effect of diltiazem on the cardiac function is not dependent upon the protection against ATP degradation in the myocardium during ischemia.

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We investigated 15 patients with gout and hyperuricemia (13 with hepatic disturbances,2 with eruption,1 with aplastic anemia and 1 with a complication of hepatic disturbance and eruption), who developed these side effects while being treated with allopurinol, and 19 patients given allopurinol who did not show side - effects (control group). There was no significant difference between the side - effect and control groups in mean duration of treatment (57.3 months) and mean dose (197mg/day). In the lymphocyte stimulation test,3 of 5 positive cases treated with allopurinol and 3 of 4 positive cases given oxipurinol had hepatic disturbances, which were regarded as side - effects. These hepatic disturbances suggest delayed allergic reaction to these drugs. No significant differences in the serum allopurinol and oxipurinol concentrations were observed between the side - effect and control groups. However, the serum oxipurinol concentration was higher in patients with low Ccr who had eruption and aplastic anemia as side - effects.

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We previously reported a case of hyperexcretion of uric acid associated with hypoexcretion of oxypurine. Probenecid - and pyrazinamide - loading tests were performed to study renal transport mechanisms for uric acid (UA), xanthine(X) and hypoxanthine (Hx)in this patient. C_UA/C_cr (uric acid creatinine clearance ratio) did not change after probenecid loading (1.0g) in this patient, while the ratio in the normal group showed a 4.0 - fold increase at 120 min. C_X/C_cr and C_HX/C_cr in this patient were half the control values at the basal state. However, two hours after probenecid loading these ratios were increased to the range of the normal group. In the normal group, C_UA/C_cr/C_cr and C_X/C_cr decreased after loading of 3.0g pyrazinamide, and C_HX/C_cr was almost unchanged. In the present case, C_UA/C_cr, C_X/C_cr and C_HX/C_cr were unchanged even after pyrazinamide loading. There was no appreciable response in uric acid excretion but an excessive response in oxypurine excretion to probenecid. Both uric acid and oxypurine showed refractoriness to pyrazinamide. These results suggest that renal handling of uric acid and oxypurine is selectively disturbed in this patient.

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The effects of 5-FU and UFT (a combination of tegafur and uracil,1: 4) on nucleotide metabolism and cell cycle were investigated in L1210 ascites tumor.5-FU (13mg/kg)and equimolar UFT(FT: 20mg/kg)were orally administered on day 3 after tumor inoculation. One and 6hr after administration of 5-FU, the intracellular dTTP pool was decreased to half the control level, but increased to 1.5 fold of the control level at 12hr. In contrast, the dTTP pool was decreased until 24hr after administration of UFT. The intracellular dCTP pool was decreased and dATP pool was increased after administration of 5-FU and UFT, but the changes in both nucleotides were greater and more prolonged after UFT administration. Cells in G0-G1 phase were decreased from 39% to about 20%, and cells in S phase were increased from 47% to about 70% after administration of both drugs, but the maximum changes were observed at 12hr after 5-FU and at 24hr after UFT administration.

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We investigated the kinetic properties and the effects of thiazole -4- carboxamide adenine dinucleotide (TAD), an active metabolite of tiazofurin, on IMP dehydrogenase in leukocytes from acute myeloid leukemia (AML) patients and on the enzyme purified from MOLT 4F cells. IMP dehydrogenase activity in human leukemic cell extracts from AML patients (33.4±0.1nmol/h/mg protein) was 11-fold increased compared to normal leukocytes (3.1±0.5). Human cultured cell lines, K 562 (47.6), BALL 1 (61.0) and MOLT 4F (45.7), also had elevated activities. Km values for IMP and NAD of leukemic IMP dehydrogenase from AML patients were 22.7 and 44.0μM, respectively. XMP showed competitive inhibition with IMP and noncompetitive inhibition with NAD. NADH showed mixed type inhibition with both IMP and NAD. The inhibitory pattern of TAD was similar to that of NADH, but the affinity of TAD to the enzyme (Ki=0.10μM) was three orders of magnitude higher than NADH (Ki=150μM). IMP dehydrogenase purified from MOLT 4F cells had similar kinetic properties (Km for IMP=29; NADH=54μM) and inhibitory mechanisms by natural products (Ki for XMP=85; NADH=94μM) and by TAD (Ki=0.075μM), as the enzyme from AML patients. These results suggest the usefulness of tiazofurin in the treatment of not only AML but also lymphoid leukemia.

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For a total of 4,654 male employees of various enterprises, the relationship between the prevalence of hyperuricemia, or the serum urate level, and the number of various factors present that are associated with hyperuricemia such as habitual alcohol consumption, obesity, hypertriglyceridemia, hypercholesterolemia and hypertension was investigated. Among the total of 4,654 cases,1,304 cases (28.0 percent) had no factors,1,922 cases (41.3 percent) had one factor and 1,428 cases (30.7 percent) had two or more factors. Out of 4,654 cases analyzed,560 cases (12.0 percent)had hyperuricemia. Among the 560 cases,84 (15.0 percent) had no factors,176 (31.4 percent) had one factor, and 300 (53.6 percent) had two or more factors. Thus, in the cases with hyperuricemia, the prevalence of cases with no factors was lower, and that with two or more factors was higher than in the total population of this sample. Among the total subjects, the prevalence of hyperuricemia was 6.4 percent (84 out of 1,304 cases) in cases without factors,9.2 percent (176 out of 1,922) in cases with one factor,17.2 percent (171 out of 997) in cases with two factors,27.3 percent (93 out of 341) in cases with three factors,39.8percent (33 out of 83) in cases with four factors, and 42.9 percent (3 out of 7) in cases with five factors. Thus, the prevalence of hyperuricemia increased as the number of factors increased. The difference in prevalence between cases with five factors and those with one factor was five-fold. As to the average level of serum urate, it was 5.46 mg/dl in the group without factors,5.65 mg/dl in the group with one factor,5.98 mg/dl in the group with two factors,6.31 mg/dl in the group with three factors,6.50mg/dl in the group with four factors, and 6.69mg/dl in the group with five factors. Thus, the average level of serum urate also increased with the increase in the number of factors. And the difference in serum urate between the group with five factors and that with one factor was 1.04mg/dl.

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