Reduced Plasma Uric Acid Research Articles

Targeting Liver Xor by GalNAc-siRNA Is an Effective Strategy for Hyperuricemia Therapy.

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy.

Effect of apheresis plasma donation on plasma uric acid levels, the lipid profile, and major plasma proteins in plasma donors in China: A multicenter, prospective cohort study

Abnormal plasma uric acid (UA) levels, the lipid profile, and plasma proteins in blood are associated with a range of adverse health outcomes. This multicenter, prospective cohort study aimed to determine the possible effects of multiple apheresis plasma donations on plasma UA levels, the lipid profile, and major proteins in plasma donors. Participants were enrolled from 1 April 2021 to 31 August 2022. When their plasma UA (men: >420 µmol/L, women: >360 µmol/L) and/or lipid levels (total cholesterol [TC]: ≥6.2 mmol/L, triglycerides [TGs]: ≥2.3 mmol/L, low-density lipoprotein cholesterol: ≥4.1 mmol/L, or high-density lipoprotein cholesterol [HDL-C]: <1.0 mmol/L) were abnormal at their first plasma donation, the enrolled participants were followed up until they had completed 10 plasma donations. A total of 11485 participants were enrolled, of whom 1861 met the inclusion criteria. During the study period, 320 donors completed 10 plasma donations. None of the participants took any corrective medicine for their abnormal index. The measured parameters were significantly different from the first to the tenth plasma donations (donors with asymptomatic hyperuricemia: UA, P < 0.001; donors with asymptomatic hyperlipidemia: HDL-C, P < 0.001; TC, P = 0.025; TGs, P < 0.001; apolipoprotein B, P = 0.025; all of the plasma donors, immunoglobulin G, P < 0.001). The levels of HDL-C, TC, and apolipoprotein B were increased, and the levels of UA, TGs, and immunoglobulin G were decreased over this time. However, immunoglobulin G levels were still in the normal range. Moreover, the changes in these parameters were closely associated with the frequency of plasma donation during the study period. Repeated apheresis plasma donations can reduce plasma UA and TG levels and increase HDL-C levels; and further evaluation of the clinical significance with a larger sample size is required.

Egg Quality, Sensory Attributes, and Protein Metabolites of Laying Hens Fed Whole Flaxseed, Fish Oil, and Different Sources of Trace Elements.

This study evaluated the effects of whole flaxseed (WFS), fish oil (FO), and different sources of Se, Zn, and Fe (inorganic, organic, and nano-source) on egg production, quality, sensory attributes, and serum protein metabolites in laying hens. A total of 144 hens were divided into six groups with six replicates of four hens each. Hens were fed six diets as follows: 1) control diet; 2) 7.5%WFS+1.5%FO; 3) 7.5%WFS+1.5%FO+175 mg/kg vitamin E (VE); 4) 7.5%WFS+1.5%FO+175 mg/kg VE + inorganic sources of Se, Zn, and Fe (ISeZnFe); 5) 7.5%WFS+1.5%FO+175 mg/kg VE + organic sources of Se, Zn, and Fe (OSeZnFe); 6) 7.5%WFS+1.5%FO+175 mg/kg VE + nano-source of Se, Zn, and Fe (NSeZnFe) from 40-50 weeks of age. Laying hens fed 7.5% WFS, 1.5% FO, and different sources of trace elements in their diets had no negative effects on laying rate, egg weight, egg mass, feed intake, feed conversion ratio, body weight change, or survival rate compared to that of hens fed the control diet. Dietary treatments did not negatively affect the external and internal egg characteristics or egg sensory attributes. Feeding 7.5%WFS+1.5%FO+VE+ISeZnFe positively influenced yolk color in fresh eggs. Dietary treatments had a significant impact on egg nutritional composition, with the highest levels of macronutrients found in eggs from hens fed the 7.5%WFS+1.5%FO+VE+NSeZnFe treatment. The highest plasma globulin concentrations were observed in hens fed organic and nano-source trace elements. The same diets reduced plasma uric acid levels. Based on these findings, the inclusion of organic or nano-source trace minerals in diets containing WFS and FO positively affected egg quality and hen protein metabolites.

Bi Xie Fen Qing Yin decoction alleviates potassium oxonate and adenine induced-hyperuricemic nephropathy in mice by modulating gut microbiota and intestinal metabolites

This study aimed to evaluate the preventive effect of Bi Xie Fen Qing Yin (BXFQY) decoction on hyperuricemic nephropathy (HN). Using an HN mouse model induced by oral gavage of potassium oxonate and adenine, we found that BXFQY significantly reduced plasma uric acid levels and improved renal function. Further study shows that BXFQY suppressed the activation of the NLRP3 inflammasome and decreased the mRNA expressions of pro-inflammatory and fibrosis-associated factors in renal tissues of HN mice. Also, BXFQY prevented the damage to intestinal tissues of HN mice, indicative of suppressed colonic inflammation and increased gut barrier integrity. By 16 S rDNA sequencing, BXFQY significantly improved gut microbiota dysbiosis of HN mice. On the one hand, BXFQY down-regulated the abundance of some harmful bacteria, like Desulfovibrionaceae, Enterobacter, Helicobacter, and Desulfovibrio. On the other hand, BXFQY up-regulated the contents of several beneficial microbes, such as Ruminococcaceae, Clostridium sensu stricto 1, and Streptococcus. Using gas or liquid chromatography-mass spectrometry (GC/LC-MS) analysis, BXFQY reversed the changes in intestinal bacterial metabolites of HN mice, including indole and BAs. The depletion of intestinal flora from HN or HN plus BXFQY mice confirmed the significance of gut microbiota in BXFQY-initiated treatment of HN. In conclusion, BXFQY can alleviate renal inflammation and fibrosis of HN mice by modulating gut microbiota and intestinal metabolites. This study provides new insight into the underlying mechanism of BXFQY against HN.

SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function.

Sodium-glucose transporter 2 (SGLT2) inhibitor-induced uric acid lowering may contribute to kidney-protective effects of the drug class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2 inhibitors in people with type 2 diabetes with a focus on urate transporter 1. We conducted an analysis of two randomized clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion, and hemodynamic kidney function were measured in the fasted state and during clamped euglycemia or hyperglycemia. Second, in the Uric Acid Excretion study, ten people with type 2 diabetes received 1 week of empagliflozin, urate transporter 1 blocker benzbromarone, or their combination in a crossover design, and effects on plasma uric acid, fractional uric acid excretion, and 24-hour uric acid excretion were measured. In the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, compared with the fasted state (5.3±1.1 mg/dl), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dl (both P<0.001) while increasing fractional uric acid excretion (by 3.2%±3.1% and 8.9%±4.5%, respectively; both P<0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8 during fasting, 1.0±1.0 in hyperinsulinemic-euglycemic state, and 0.8±0.7 mg/dl during hyperglycemic conditions (P<0.001), respectively, whereas fractional uric acid excretion in 24-hour urine increased by 3.0%±2.1% (P<0.001) and 2.6%±4.5% during hyperinsulinemic-euglycemic conditions (P=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (r=0.35; P=0.02). In the Uric Acid Excretion study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy. In conclusion, SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and is attenuated during concomitant pharmacologic blockade of urate transporter 1. Renoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED), NCT02682563; SGLT2 Inhibition: Uric Acid Excretion Study (UREX), NCT05210517.

Box-Behnken optimisation of growth performance, plasma metabolites and carcass traits as influenced by dietary energy, amino acid and starch to lipid ratios in broiler chickens.

A Box-Behnken designed study was completed to predict growth performance, carcass characteristics and plasma hormone and metabolite levels as influenced by dietary energy, amino acid densities and starch to lipid ratios in male broiler chickens. The design comprised three dietary energy densities (11.25, 12.375 and 13.5 MJ/kg), three digestible lysine concentrations (9.2, 10.65 and 12.1 g/kg) and three starch to lipid ratios (4.5, 12.25 and 20.0) in broiler diets based on maize and soybean meal. Each of thirteen dietary treatments was offered to 10 replicates of 15 birds per replicate floor pen or a total of 1,950 Ross 308 male broiler chickens from 21 to 35 days post-hatch. Increasing dietary energy decreased feed intake with a quadratic relationship between feed intake and dietary standardised ileal digestible (SID) Lys concentrations, where increasing SID Lys initially increased and then depressed feed intake. Increasing dietary amino acid density increased body weight gain and carcass weight; however, dietary energy did not influence body weight gain, carcass and breast meat weight. Feed efficiency was positively influenced by energy and amino acid densities but negatively influenced by starch to lipid ratios and energy and amino acids had more pronounced impacts than starch to lipid ratios. This study indicated that both energy and amino acid densities regulate feed intakes in broiler chickens. Body weight gain of modern broiler chickens is more responsive to amino acid densities; nevertheless, dietary energy density continues to play an important role in protein utilisation, as reflected in significantly reduced plasma uric acid levels.

Pharmacological mechanisms of the water leaves extract of Lysiphyllum strychnifolium for its anti-inflammatory and anti-hyperuricemic actions for gout treatment

Background: There have been anecdotal reports from Thai hyperuricemic patients that the leaves of Lysiphyllum strychnifolium could reduce plasma uric acid level and relieve inflammation of gout. However, no research to support these effects has been conducted. Objectives: This study was aimed to evaluate the anti-inflammatory and hypouricemic effects of L. strychnifolium leaves extract and to investigate the pharmacological mechanisms of these effects. Materials and Methods: The anti-inflammatory effect of L. strychnifolium was evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Effects of L. strychnifolium on xanthine oxidase (XO) were examined in vitro and in vivo using potassium oxonate (PO)-induced hyperuricemic mice. In addition, the antioxidant activity of L. strychnifolium was determined. Results: L. strychnifolium significantly reduced the mRNA expression of cyclooxygenase-II, inducible nitric oxide synthase, transforming growth factor-β, and tumor necrosis factor-α in LPS-stimulated RAW 264.7 cells (P Abbreviations used: ABTS: 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid); COX-II: Cyclooxygenase-II; DMEM: Dulbecco's modified Eagle medium; DPPH: 2,2-Diphenyl-1-picrylhydrazyl; FBS: Fetal bovine serum; FRAP: Ferric reducing antioxidant power; GAE: Gallic acid equivalence; GLUT9: Glucose transporter 9; iNOS: Inducible nitric oxide synthase; LPS: Lipopolysaccharide; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PO: Potassium oxonate; P/S: Penicillin/streptomycin; QE: Quercetin equivalent; SLC22A12: Solute carrier family 22 member 12; TNF-α: Tumor necrosis factor-α; TGF-β: Transforming growth factor-β; URAT: Urate-anion transporter 1; XO: Xanthine oxidase.

Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone.

Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo. In human embryonic kidney (HEK)293 cells overexpressing URAT1, organic anion transporter 1 (OAT1), and OAT3, benzbromarone inhibited all transporters similarly, whereas UR-1102 inhibited URAT1 comparably to benzbromarone but inhibited OAT1 and OAT3 quite modestly. UR-1102 at 3-30 mg/kg or benzbromarone at 3-100 mg/kg was administered orally once a day for 3 consecutive days to tufted capuchin monkeys, whose low uricase activity causes a high plasma urate level. When compared with the same dosage of benzbromarone, UR-1102 showed a better pharmacokinetic profile, increased the fractional excretion of urinary uric acid, and reduced plasma uric acid more effectively. Moreover, the maximum efficacy of UR-1102 was twice that of benzbromarone, suggesting that selective inhibition of URAT1 is effective. Additionally UR-1102 showed lower in vitro potential for mechanisms causing the hepatotoxicity induced by benzbromarone. These results indicate that UR-1102 achieves strong uricosuric effects by selectively inhibiting URAT1 over OAT1 and OAT3 in monkeys, and could be a novel therapeutic option for patients with gout or hyperuricemia.

A Randomized Controlled Trial of the Effects of Febuxostat Therapy on Adipokines and Markers of Kidney Fibrosis in Asymptomatic Hyperuricemic Patients With Diabetic Nephropathy.

Background:In observational studies, higher uric acid levels are associated with metabolic syndrome, diabetes, and kidney disease.Objective:The objective of this study is to examine whether reduction of plasma uric acid with febuxostat, a xanthine oxido reductase inhibitor, impacts adipose tissue oxidative stress, adipokines, and markers of systemic inflammation or kidney fibrosis.Design:This was a double-blinded randomized controlled trial.Setting:Academic university setting was used.Patients:Overweight or obese adults with hyperuricemia and type 2 diabetic nephropathy were included.Measurements:Adipose tissue thiobarbituric acid reducing substances (TBARS) and adiponectin concentrations and urinary transforming growth factor–β (TGF-β) were primary endpoints. Plasma C-reactive protein, high molecular weight–adiponectin, interleukin–6, tumor necrosis factor–α, and TBARS and albuminuria were among predefined secondary endpoints.Methods:Participants were randomly assigned to febuxostat (n = 40) or matching placebo (n = 40) and followed for 24 weeks.Results:Baseline plasma uric acid levels were 426 ± 83 µmol/L; 95% completed the study. Estimated glomerular filtration rate (eGFR) declined from 54 ± 17 mL/min/1.73 m2 at baseline to 51 ± 17 mL/min/1.73 m2 at 24 weeks (P = .05). In separate mixed-effects models, compared with placebo, febuxostat reduced uric acid by 50% (P < .001) but had no significant effects on subcutaneous adipose tissue TBARS (−7.4%, 95% confidence interval [CI], 57.4%-101.4%) or adiponectin (6.7%, 95% CI, 26.0%-53.8%) levels or urinary TGF-β/creatinine ratio (18.0%, 95% CI, 10.0%-54.8%) or secondary endpoints.Limitations:Relatively modest sample size and short duration of follow-up.Conclusions:In this population with progressive diabetic nephropathy, febuxostat effectively reduced plasma uric acid. However, no detectable effects were observed for the prespecified primary or secondary endpoints.Trial Registration:The study was registered in clinicaltrials.gov (NCT01350388).

Evaluation of Xanthine Oxidase Inhibitory Potential and In vivo Hypouricemic Activity of Dimocarpus longan Lour. Extracts.

Background:Longan is a fruit tree known to contain many phenolic components, which are capable of protecting people from oxidative damage through an anti-inflammatory mechanism. It may be also worthwhile to study the effect on lowering uric acid activity.Materials and Methods:This study investigates the lowering of uric acid using longan extracts, including flowers, pericarps, seeds, leaves, and twigs, on potassium-oxonate-induced hyperuricemia mice and its inhibitory actions against xanthine oxidase (XO) activities.Results:The findings revealed that ethyl acetate fraction of longan extracts exhibited strong XO-inhibitory activity, and the flower extracts (IC50 = 115.8 μg/mL) revealed more potent XO-inhibitory activity to those of pericarps (118.9 μg/mL), twigs (125.3 μg/mL), seeds (262.5 μg/mL), and leaves (331.1 μg/mL) in vitro. In addition, different dosages of longan extract (50–100 mg/kg) were administered to hyperuricemic mice. The lowering effect of longan extracts on uric acid at 75 mg/kg markedly reduced plasma uric acid levels in decreasing order: Flowers (80%) > seeds (72%) > pericarps (64%) > twigs (59%) > leaves (41%), compared with allopurinol (89%). Finally, 10 isolated phytochemicals from longan flowers were then examined in vitro. The results indicated that proanthocyanidin A2 and acetonylgeraniin A significantly inhibited XO activity in vitro. This is the first report providing new insights into the urate-reducing effect of phenolic dimer and hydrolyzable tannin, which can be developed to potential hypouricemic agents.SUMMARY Longan flower extracts possess more potent XO-inhibitory activity than pericarps, twigs, seeds, and leaves in vitroThe lowering effect of longan flowers and seeds extracts markedly reduced plasma uric acid levels as compared to allopurinol in vivoThe extract proanthocyanidin A2 and acetonylgeraniin A were demonstrated potent XO inhibitory activity in vitro Abbreviations used: PO: Potassium-oxonate, XO: xanthine oxidase, HE: n-hexane, EA: ethyl acetate, i.p.: intraperitoneal, PBS: phosphate-buffered saline, AP: allopurinol, PUA: plasma uric acid.

Effects of dietary substitution of zinc-methionine for inorganic zinc sources on growth performance, tissue zinc accumulation and some blood parameters in broiler chicks.

This study was designed to evaluate the effects of dietary inclusion of zinc-methionine (ZnMet) as a replacement for conventional inorganic zinc sources on performance, tissue zinc accumulation and some plasma indices in broiler chicks. A total of 450-day-old Ross male broiler chicks were randomly assigned to five pen replicates of nine experimental diets. Dietary treatments consisted of two basal diets supplemented with 40 mg/kg added Zn as feed-grade Zn sulphate or Zn oxide in which, Zn was replaced with that supplied from ZnMet complex by 25, 50, 75 or 100%. At 42 days of age, three randomly selected birds from each pen were bled to measure plasma metabolites; then, the chicks were slaughtered to evaluate carcass characteristics. Results showed that dietary treatments affected (p < 0.05) feed intake during the starter period, and chicks on Zn oxide diets consumed more feed than sulphate counterparts. Furthermore, dietary substitution of inorganic Zn sources by ZnMet caused improvements (p < 0.01) in body weight gain during all experimental periods. Dietary supplementation of ZnMet improved feed conversion efficiency during 1-21 and 1-42, but not in 21-42 days of age. Complete replacement of inorganic Zn by that supplied from ZnMet caused an increase (p < 0.05) in relative liver weight. Similarly, dietary inclusion of ZnMet increased breast meat and carcass yields and reduced abdominal fat percentage (p < 0.05). Incremental levels of ZnMet increased (p < 0.05) zinc concentrations in liver and thymus, and the highest zinc accumulations were seen in 100% ZnMet-supplemented birds. Interestingly, introduction of ZnMet into the diets partially in place of inorganic sources resulted in decreases (p < 0.01) in plasma uric acid and triglycerides concentrations. The present findings indicated that dietary ZnMet inclusion in replacement of inorganic sources in addition to improving growth performance, reduced plasma uric acid and triglycerides concentrations, consequently decreased abdominal fat pad and increased carcass meat yield.

Effects of allopurinol on plasma uric acid levels in normouricaemic and hyperuricaemic green iguanas (Iguana iguana)

A two-phase cross-over therapeutic study was performed with 19 green iguanas (Iguana iguana) maintained within a preferred optimum temperature range of 26 to 37°C. During phase 1, they were fed...

Xanthine oxidase does not contribute to impaired peripheral conduit artery endothelium‐dependent dilatation with ageing

Vascular oxidative stress is the key mechanism involved in the age-related decline in endothelium-dependent dilatation (EDD). We tested the hypothesis that xanthine oxidase (XO), a major vascular source of reactive oxygen species, contributes to the impairment in EDD with ageing. At baseline, brachial artery flow-mediated dilatation (FMD) was 55% lower in older (n = 9, 64 +/- 2 years, 8M/1F, mean +/- S.E.M.) versus young (n = 9, 26 +/- 1 years, 8M/1F) healthy adults (3.41 +/- 0.44 versus 7.53 +/- 0.67%, P < 0.001), whereas endothelium-independent dilatation (EID; sublingual nitroglycerin) did not differ between groups. Plasma oxidized low-density lipoprotein (oxi-LDL), a measure of systemic oxidative stress, was greater at baseline in the older subjects (58.3 +/- 5.9 versus 46.8 +/- 2.4 U l(-1), P < 0.05) and inversely correlated with baseline FMD (r = - 0.54; P < 0.05). Acute administration of allopurinol, a competitive inhibitor of XO, reduced plasma uric acid concentrations similarly in both groups (P < 0.001), but did not affect FMD, EID, or oxi-LDL in either group. Vascular endothelial protein expression of XO (immunofluorescence) was not different in antecubital venous cells from the young and older subjects (0.56 +/- 0.12 versus 0.68 +/- 0.19 XO intensity/human umbilical vein endothelial cell intensity, P = 0.49). We conclude that XO does not contribute to oxidative stress-associated reductions in peripheral conduit artery EDD with ageing in humans, possibly due to an absence of age-associated up-regulation of endothelial XO.

Effects of a fenofibrate/losartan combination on the plasma concentration and urinary excretion of purine bases

To assess the effects of a combination of fenofibrate and losartan on the plasma concentrations and urinary excretion of purine bases in healthy male subjects. 5 healthy males participated in a fenofibrate plus losartan combination study. The plasma concentrations and urinary excretion of purine bases (hypoxanthine, xanthine, uric acid) were measured before and after administrations of losartan (100 mg o.d.) alone for 2 weeks, losartan and fenofibrate together for 2 weeks and fenofibrate (300 mg o.d.) alone for 2 weeks, which were given consecutively over a 6-week period. Losartan alone significantly reduced the serum uric acid concentration and increased uric acid excretion, whereas the combination of losartan and fenofibrate reduced serum uric acid concentrations further with a concomitant increased uric acid excretion. Fenofibrate alone also reduced plasma uric acid concentration with an increase in urinary excretion, although the effect was weak when compared with the combination treatment. The plasma concentrations and urinary excretion of oxypurines remained unchanged throughout the entire study. A combination of fenofibrate and losartan demonstrated an additive urate-lowering effect which may be beneficial in the treatment of patients with gout and hypertriglyceridemia.

Investigations into the uricolytic properties of urate oxidase in a granivorous ( Columba livia domestica ) and in a carnivorous ( Buteo jamaicensis ) avian species

To study the uricolytic properties of urate oxidase in granivorous and carnivorous birds, experiments were conducted in pigeons ( Columba livia domestica ) and Red-tailed Hawks ( Buteo jamaicensis ). Plasma concentrations of allantoin and uric acid were determined at various times in experimental groups before and after receiving 100, 200, and 600 U/kg urate oxidase once daily and were compared with controls. All regimens caused a significant decrease in plasma uric acid concentrations within 2 days after the first administration, when compared with controls. Furthermore, both doses used in Red-tailed Hawks (200 and 100 U/kg) caused a significant postprandial suppression of plasma uric acid concentrations. Plasma allantoin concentrations were significantly higher when compared with controls. The ability of urate oxidase to prevent the physiological postprandial hyperuricaemia in Red-tailed Hawks and to reduce plasma uric acid concentrations to undetectable levels, shows the great potential of this drug for treating avian hyperuricaemia.

Further studies on the use of allopurinol to reduce plasma uric acid concentrations in the Red-tailed Hawk ( Buteo jamaicensis ) hyperuricaemic model

The present paper reports the effects of allopurinol in a raptor hyperuricaemic model. The study was performed as a follow-up to previous experiments wherein allopurinol was used in doses of 100 and 50 mg/kg, and was proved to be toxic at these higher dose rates. To investigate whether 25 mg/kg (semel in die) s.i.d. allopurinol is a safe and effective dose in Red-tailed Hawks ( Buteo jamaicensis ) to reduce plasma uric acid concentrations, experimental studies were performed using the physiologically occurring postprandial hyperuricaemia. Preprandial and postprandial plasma concentrations of xanthine, hypoxanthine, allopurinol, oxypurinol and uric acid were established by high-performance liquid chromatography at various time intervals after receiving allopurinol (25 mg/kg SID) or placebo. No significant differences were observed between the experimental and the control group. These results indicate that this dose is safe to administer; however, this dose failed to cause a significant effect on plasma uric acid concentrations. Because of the low therapeutic ratio of allopurinol in Red-tailed Hawks, follow-up studies have concentrated on an alternative for the treatment of hyperuricaemia, namely urate oxidase.

Mechanism of the uricosuric action of E3040, a drug used to treat inflammatory bowel disease II: study using DBA/2N mice.

In the initial phase of clinical studies, it was shown that E3040, a new type of anti-inflammatory drug, reduced plasma uric acid levels. The present study describes a comparison of the excretion of uric acid in the proximal tubules of the kidney after administration of E3040 and its conjugates, sulphate and glucuronide, with that of other general uricosuric agents in DBA/2N mice. The aim of this investigation was to elucidate the mechanism for the uricosuric action of E3040. It was found that E3040 increased the excretion rate of uric acid in a dose-dependent manner, and the excretion rates following 10 and 50 mg/kg doses were significantly greater than that of the control group. The paradoxical effect observed with probenecid was not seen in the E3040 dose-response curve for the uric acid excretion rate. Neither E3040-sulphate nor E3040-glucuronide increased the excretion rate of uric acid significantly, even at a high dose, such as 200 mg/kg. In the pyrazinoic acid suppression test, the uric acid excretion rate after concomitant administration of E3040 and pyrazinoic acid was significantly higher than that after administration of pyrazinoic acid alone, and the rate after concomitant administration was 30% of the level after administration of E3040 alone. The change in the excretion rate of uric acid after concomitant administration of E3040 and pyrazinoic acid was similar to that of AA193, a selective inhibitor of the presecretory reabsorption of uric acid. From these results, it appears that E3040 may exert its uricosuric action by reducing the presecretory reabsorption of uric acid rather than increasing its secretion.

Effect of sulphinpyrazone (Anturan) on uric acid excretion and plasma uric acid concentration in healthy volunteers.

Investigations in six healthy volunteers given single oral doses of sulphinpyrazone (Anturan) showed that the drug had a potent uricosuric effect, even if the concentration of uric acid in the plasma was normal. In the dose range tested of 50 to 800 mg the increase in uric acid excretion was dose-related. It reached a maximum within 2 h and was still detectable 6--8 h after the drug was taken. There was a corresponding dose-related reduction in the plasma concentration of uric acid, which reached its lowest level after 8--10 h. The administration of 300 mg twice daily for four days to a further five healthy volunteers reduced plasma uric acid from 5.06 to 1.8 mg%. The findings indicate that, even if plasma uric acid levels are unknown, it would be advisable to avoid the risk of formation of urinary calculi by administering sulphinpyrazone in gradually increasing doses, ensuring adequate fluid intake and alkalinizing the urine during the first few days of treatment.