Administration Of Uric Acid Research Articles

Gout

In most cases gout is the clinical manifestation of familial hyperuricemia. Pathogenesis of hyperuricemia, clinical manifestations, diagnosis and differential diagnosis of hyperuricemia and gout are described. Treatment of hyperuricemia consists of dietary measurements and administration of uric acid lowering drugs, such as allopurinol or uricosuric agents. Nonsteroidal antiinflammatory drugs, colchicine and glucocorticosteroids are the treatment of choice for the acute gout attack. Prophylaxis of acute uric acid nephropathy consists of hydration, urine alkalinization and administration of allopurinol or rasburicase. For treatment of acute uric acid nephropathy rasburicase is the drug of choice.

Uric acid administration for neuroprotection in patients with acute brain ischemia

Uric acid is the end product of purine metabolism and a powerful water-soluble antioxidant and radical scavenger in humans whose generation is increased in situations of oxidative stress, such as brain ischemia. Although hyperuricemia has been related to an increased risk of cardiovascular events, the association was not found significant in many studies after adjustment for the effect of confounders. In the ischemic rat brain, the administration of uric acid results in neuroprotection and improved behavioral outcome. The severity of neurological impairment and the volume of infarction in patients with stroke have been found inversely related to the concentration of uric acid. In healthy volunteers, uric acid has been administered without untoward effects to show a conspicuous reduction of oxidative stress. We hypothesize that the administration of uric acid could be beneficial and cost effective in patients sustaining acute oxidative stress, such as those with acute ischemic stroke. Uric acid could also extend to more than 3 h the therapeutic window of rt-PA after stroke and it could limit the appearance of neurobehavioral changes after cardiopulmonary bypass. Prospective double blind randomized controlled trials are needed to test the value of uric acid in these clinical settings in which oxyradical formation is prominent.

Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors.

Uric acid (UA) is a purine metabolite that selectively inhibits peroxynitrite-mediated reactions implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative diseases. Serum UA levels are inversely associated with the incidence of MS in humans because MS patients have low serum UA levels and individuals with hyperuricemia (gout) rarely develop the disease. Moreover, the administration of UA is therapeutic in experimental allergic encephalomyelitis (EAE), an animal model of MS. Thus, raising serum UA levels in MS patients, by oral administration of a UA precursor such as inosine, may have therapeutic value. We have assessed the effects of inosine, as well as inosinic acid, on parameters relevant to the chemical reactivity of peroxynitrite and the pathogenesis of EAE. Both had no effect on chemical reactions associated with peroxynitrite, such as tyrosine nitration, or on the activation of inflammatory cells in vitro. Moreover, when mice treated with the urate oxidase inhibitor potassium oxonate were fed inosine or inosinic acid, serum UA levels were elevated markedly for a period of hours, whereas only a minor, transient increase in serum inosine was detected. Administration of inosinic acid suppressed the appearance of clinical signs of EAE and promoted recovery from ongoing disease. The therapeutic effect on animals with active EAE was associated with increased UA, but not inosine, levels in CNS tissue. We, therefore, conclude that the mode of action of inosine and inosinic acid in EAE is via their metabolism to UA.

Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease

Peroxynitrite has been implicated in the pathogenesis of multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). Previously, we have shown that administration of uric acid (UA), a peroxynitrite scavenger, is therapeutic in EAE We have also shown that MS patients have lower levels of serum uric acid than healthy individuals or those with other neurological diseases. The aim of this investigation was therefore to raise serum UA levels in MS patients. Oral administration of UA failed to increase low serum UA levels, evidently due to its degradation by gastrointestinal bacteria. However, serum UA could be raised and maintained at elevated levels for a year and more without reported side-effects by oral administration of its precursor inosine. Three of 11 patients given inosine showed some evidence of clinical improvement and there was no sign of disease progression in the remaining patients. Gadolinium-enhanced lesions, observed in two patients before receiving inosine, could not be detected after either 10 or IS months inosine treatment These data provide evidence that serum UA levels can be readily manipulated and that the benefit of higher levels to individuals with MS should be studied further in greater number of patients.

The central nervous system inflammatory response to neurotropic virus infection is peroxynitrite dependent.

We have recently demonstrated that increased blood-CNS barrier permeability and CNS inflammation in a conventional mouse model of experimental allergic encephalomyelitis are dependent upon the production of peroxynitrite (ONOO(-)), a product of the free radicals NO* and superoxide (O2*(-)). To determine whether this is a reflection of the physiological contribution of ONOO(-) to an immune response against a neurotropic pathogen, we have assessed the effects on adult rats acutely infected with Borna disease virus (BDV) of administration of uric acid (UA), an inhibitor of select chemical reactions associated with ONOO(-). The pathogenesis of acute Borna disease in immunocompetent adult rats results from the immune response to the neurotropic BDV, rather than the direct effects of BDV infection of neurons. An important stage in the BDV-specific neuroimmune response is the invasion of inflammatory cells into the CNS. UA treatment inhibited the onset of clinical disease, and prevented the elevated blood-brain barrier permeability as well as CNS inflammation seen in control-treated BDV-infected rats. The replication and spread of BDV in the CNS were unchanged by the administration of UA, and only minimal effects on the immune response to BDV Ags were observed. These results indicate that the CNS inflammatory response to neurotropic virus infection is likely to be dependent upon the activity of ONOO(-) or its products on the blood-brain barrier.

Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo.

Uric acid is a well-known natural antioxidant present in fluids and tissues throughout the body. Oxyradical production and cellular calcium overload are believed to contribute to the damage and death of neurons that occurs following cerebral ischemia in victims of stroke. We now report that uric acid protects cultured rat hippocampal neurons against cell death induced by insults relevant to the pathogenesis of cerebral ischemia, including exposure to the excitatory amino acid glutamate and the metabolic poison cyanide. Confocal laser scanning microscope analyses showed that uric acid suppresses the accumulation of reactive oxygen species (hydrogen peroxide and peroxynitrite), and lipid peroxidation, associated with each insult. Mitochondrial function was compromised by the excitotoxic and metabolic insults, and was preserved in neurons treated with uric acid. Delayed elevations of intracellular free calcium levels induced by glutamate and cyanide were significantly attenuated in neurons treated with uric acid. These data demonstrate a neuroprotective action of uric acid that involves suppression of oxyradical accumulation, stabilization of calcium homeostasis, and preservation of mitochondrial function. Administration of uric acid to adult rats either 24 hr prior to middle cerebral artery occlusion (62.5 mg uric acid/kg, intraperitoneally) or 1 hr following reperfusion (16 mg uric acid/kg, intravenously) resulted in a highly significant reduction in ischemic damage to cerebral cortex and striatum, and improved behavioral outcome. These findings support a central role for oxyradicals in excitotoxic and ischemic neuronal injury, and suggest a potential therapeutic use for uric acid in ischemic stroke and related neurodegenerative conditions.

Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis.

Uric acid, the naturally occurring product of purine metabolism, is a strong peroxynitrite scavenger, as demonstrated by the capacity to bind peroxynitrite but not nitric oxide (NO) produced by lipopolysaccharide-stimulated cells of a mouse monocyte line. In this study, we used uric acid to treat experimental allergic encephalomyelitis (EAE) in the PLSJL strain of mice, which develop a chronic form of the disease with remissions and exacerbations. Uric acid administration was found to have strong therapeutic effects in a dose-dependent fashion. A regimen of four daily doses of 500 mg/kg uric acid was required to promote long-term survival regardless of whether treatment was initiated before or after the clinical symptoms of EAE had appeared. The requirement for multiple doses is likely to be caused by the rapid clearance of uric acid in mice which, unlike humans, metabolize uric acid a step further to allantoin. Uric acid treatment also was found to diminish clinical signs of a disease resembling EAE in interferon-gamma receptor knockout mice. A possible association between multiple sclerosis (MS), the disease on which EAE is modeled, and uric acid is supported by the finding that patients with MS have significantly lower levels of serum uric acid than controls. In addition, statistical evaluation of more than 20 million patient records for the incidence of MS and gout (hyperuricemic) revealed that the two diseases are almost mutually exclusive, raising the possibility that hyperuricemia may protect against MS.

Decreased serum concentrations of 1,25(OH)2-vitamin D3 in patients with gout.

We measured the serum concentrations of 1,25(OH)2-vitamin D3, 25(OH)-vitamin D3, parathyroid hormone (PTH) in 82 male patients with primary gout whose serum uric acid was significantly higher than that of 41 normal control male subjects (8.8 +/- 0.2 vs 5.6 +/- 0.2 mg/dL, p < 0.001). The serum 1,25(OH)2-vitamin D3 concentration was significantly lower in the patients with gout compared with the control subjects (39.6 +/- 1.4 vs 44.8 +/- 1.7 pg/mL, p < 0.05), while no differences were observed between the two groups in either the serum concentration of 25(OH)-vitamin D3 or PTH. The administration of uric acid lowering agent to the patients for 1 year caused a significant increase in their serum 1,25(OH)2-vitamin D3 concentration which was associated with a significant decrease in their serum uric acid concentration. In contrast, the serum concentrations of 25(OH)-vitamin D3 and PTH were not affected by these drugs. These results suggest that uric acid per se may directly decrease the serum concentration of 1,25(OH)2-vitamin D3 in patients with gout by inhibiting 1-hydroxylase activity.

Frequent administration of uric acid extends survival of fasting analbuminemic rats under cold environment.

Analbuminemic rats died within 18 h after a rapid decrease of body temperature whereas control Charles River, Wistar, and Sprague Dawley rats survived for 40 h, when the animals were kept at 5 degrees C without food. Five low molecular weight fractions obtained from Sprague Dawley rat sera were administered to analbuminemic rats kept under these conditions. The duration of survival was extended by the administration of two of the fractions. Several characteristics of one of these fractions coincided with those of uric acid, and body temperature of analbuminemic and Sprague Dawley rats increased within 5 min after uric acid administration.

Ocular hyperuricosis in the rabbit following hyperuricemia and topical epinephrine.

Sources for the high levels of uric acid reported in the aqueous humor from human glaucoma eyes were studied in the rabbit model. A hyperuricemia was produced by oxonic acid blockade of uricase prior to a systemic administration of uric acid. These animals showed no increase in aqueous humor uric acid. Topical medication of eyes with 1% epinephrine produced a statistically significant (P less than 0.001) rise in the level of uric acid in aqueous humor of treated eyes. Mean urate levels increased from 0.44 mg/dl to 0.82 mg/dl. Topical glaucoma medication appears to be the source of ocular hyperuricosis.

Uricolysis by human leukocytes.

ALTHOUGH uricase is absent from the tissues of the human being, there is nevertheless evidence that uric acid is destroyed in man. Benedict, Forsham and Stetten1 first demonstrated by intravenous injection of isotopically labelled urate that only two-thirds to three-fourths of the daily urate turn-over of the body actually appears as urinary uric acid. Furthermore, the total recovery of the injected isotopically labelled uric acid in urinary uric acid over a 7-day period is similarly reduced2. The missing isotope has been demonstrated in a variety of metabolites in the urine, including ammonia, urea, allantoin, allantoic acid, respiratory carbon dioxide and faecal bacterial bodies, after intravenous administration of uric acid labelled with nitrogen-15 and uric acid-2-14C (refs. 3, 4).

Uric acid metabolism in hepatolenticular degeneration.

SummaryIt has been found that in patients with hepatolenticular degeneration (Wilson's disease) the level of uric acid in the serum is reduced and the amount of uric acid excreted in the urine is increased. Following the intravenous administration of uric acid, such patients excrete uric acid in the urine more rapidly than do normal subjects. No correlation was observed between the excretion of copper and that of uric acid. It is suggested that the alterations in uric acid metabolism are due to an inability of the renal tubules to reabsorb uric acid efficiently.