Reduce Serum Urate Research Articles

Febuxostat, a novel drug for the treatment of hyperuricemia of gout

Febuxostat is a novel, nonpurine, selective inhibitor of xanthine oxidase (NP-SIXO), recently approved in the European Union. Febuxostat shows high, long-term efficacy for the reduction of serum urate (SU) levels, showing linear pharmacokinetics at approved doses, and its pharmacokinetics are not clinically significantly influenced by the presence of mild-to-moderate renal or liver function impairment. The clinical applicability of febuxostat should have a significant impact in patients with the highest baseline SU levels, the most severe gout, previous adverse events with other urate-lowering drugs or no availability of alternative urate-lowering drugs after failure to properly control SU levels during urate-lowering therapy. Febuxostat may become an interesting choice in our use of xanthine oxidase inhibitors.

Efficacy and safety of allopurinol in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a genetic disease of purine metabolism resulting in uric acid overproduction. Allopurinol, which inhibits the enzyme xanthine oxidase and reduces uric acid synthesis, is widely used for the treatment of gout and uric acid overproduction. The aim of the study was to analyze the long-term efficacy and safety of allopurinol in patients with HPRT deficiency. Nineteen patients (13 with Lesch-Nyhan syndrome and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.4 mg/kg body weight per day; range, 3.7-9.7 mg/kg body weight per day) and followed up for at least 12 months (mean follow-up, 7.6 years). The efficacy of allopurinol was evaluated by serial measurement of purine metabolic parameters and renal function as well as by clinical manifestations. Safety was assessed by recording adverse events. Treatment with allopurinol normalized serum urate level in all patients and resulted in a mean reduction in serum urate of 47%. Allopurinol treatment was associated with a mean 74% reduction in urinary uric acid-to-creatinine ratio. In contrast, allopurinol treatment increased mean hypoxanthine and xanthine urinary excretion rates 5.4- and 9.5-fold, respectively, compared with baseline levels. The decrease in uric acid excretion in complete and partial HPRT-deficient patients was not accompanied by a stoichiometric substitution of hypoxanthine and xanthine excretion rates. Allopurinol-related biochemical changes were similar in patients with either complete or partial HPRT deficiency. Renal function remained stable or improved with treatment. Three patients had urolithiasis during allopurinol treatment. In 2 patients, xanthine stones were documented and they required allopurinol dose adjustments aimed at reducing excessive oxypurine excretion rates. No allopurinol hypersensitivity reactions occurred. Neurologic manifestations were not influenced by allopurinol therapy. In conclusion, allopurinol is efficacious and generally safe for the treatment of uric acid overproduction in patients with HPRT deficiencies. Xanthine lithiasis, developing as a consequence of allopurinol therapy, should be preventable by adjustment of allopurinol dose.

Gout Is on the Rise; Improved Treatments Needed

Sharon Worcester is with the Southeast bureau of Elsevier Global Medical News. DESTIN, FLA. — The incidence of gout is on the rise, and lifestyle factors are largely to blame, according to Dr. N. Lawrence Edwards, professor and vice chairman of the department of medicine at the University of Florida, Gainsville. For example, one study showed that between 1977–1978 and 1995–1996, the annual rate of primary gout more than doubled, from about 16 cases/100,000 population to nearly 42 cases/100,000 population. Factors that appear to play a role in this incidence spike are greater longevity, widespread diuretic and aspirin use, hypertension incidence, obesity, metabolic syndrome, and dietary trends, Dr. Edwards said at the annual Rheumatology on the Beach. Certain dietary factors affect the risk for gout (high consumption of meat, seafood, and beer increase risk, and high intake of dairy is protective, for example); other risk factors are modifiable (such as obesity and hypertension). However, despite the association between lifestyle factors and risk, their modification will not eliminate existing gout. Weight reduction, decreased alcohol consumption, and reduced intake of purine-rich foods (which have been linked with gout) will reduce urate levels only by about 1 mg/dL. Urate-lowering therapy, which 15 years ago was reserved for use only in patients with chronic gout, now is considered warranted following the first one or two acute attacks, he noted. Treatment goals for gout include termination of the attack as rapidly as possible, prevention of future attacks by reducing the chance of crystal-induced inflammation, and long-term correction of metabolic problems with a goal of lowering serum urate to below 6 mg/dL to allow depletion of the total body uric acid pool. Uricosuric agents, such a probenecid, and the xanthine oxidase inhibitor allopurinol are used for this purpose. These agents are used for reducing urate levels—the most common physiologic abnormality found in gout patients—but uricosuric agents increase the risk of uric acid crystallization in the urine and associated stone formation. A number of other agents, such as ampicillin, penicillin, cephradine, heparin, and rifampicin, can potentially affect the action of uricosuric agents, Dr. Edwards said. Allopurinol, which is a purine analog that is both a substrate and inhibitor of xanthine oxidase, is effective both for people who overproduce and for those who underexcrete xanthine oxidase. The drug also has the convenience of single daily dosing, and it can be efficacious in patients with renal insufficiency. However, allopurinol isn't always effective for achieving target serum urate levels. In one study of patients treated daily with a 300-mg dose, only about half achieved a serum urate level of 6 mg/dL, and in an observational study of nearly 6,000 patients, median serum urate levels decreased from 8.7 mg/dL to 7.1 mg/dL. Although dosing up to 800 mg/day is acceptable, concerns about intolerance based on reports of severe hypersensitivity syndrome, rash, gastrointestinal problems, increases in liver enzymes, and rare bone marrow suppression, tend to scare physicians away from prescribing higher doses, he noted. As with uricosuric agents, drug-drug interactions also are a problem with allopurinol. Keys to effective treatment with this drug include dosing allopurinol to achieve a serum urate level between 5.0 and 6.0 mg/dL, which allows reduction of total body urate pool and mobilization of deposited crystals, Dr. Edwards said, stressing the need to start at a low dose of 50–100 mg/day, with close monitoring of escalation. If the target serum urate level is reached, therapy should be ongoing; intermittent therapy or withdrawal will lead to recurrence of acute attacks within 6 months, and development of tophi within a few years. Allopurinol shouldn't be started during an acute attack and shouldn't be stopped in those already on treatment. Also keep in mind that these medications will not control the pain of gout, and pain medications will do nothing to reduce serum urate, he advised. New urate-lowering agents that improve compliance and are useful in those with allopurinol intolerance and renal failure are needed, as are options for those taking other drugs that interact with allopurinol and uricosuric agents, he concluded.

Renal salt wasting without cerebral disease: Diagnostic value of urate determinations in hyponatremia

CASE PRESENTATION A 76-year-old woman, who sustained an accidental fracture of the femoral neck, developed hyponatremia after admission. The diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was made by the consulting internist and fluid restriction of 700 cc/day was instituted. Her serum sodium (Na) fluctuated between 122 and 129mmol/l and a renal consultation was requested on the eighth day after undergoing a hemiarthroplasty of the hip when she was ambulating and on no pain medication. Her blood pressure was 100/60 mm Hg, pulse 92 beats/min and there was poor tissue turgor, flat jugular veins, and dry mucous membranes. There was no edema, third spacing, postural hypotension or neurological abnormalities. Her medications included docusate sodium, milk of magnesia, simvastatin, and warfarin. She was not on drugs such as atorvastatin, fenofibrate, or losartan which reduce serum urate by increasing renal urate excretion. 1-3 A low baseline urine Na (UNa) concentration of 6 mmol/l suggested a hypovolemic condition with normal renal function 4 that should result in a prerenal state characterized by low UNa, azotemia, and hyperuricemia. The baseline serum urate of 3.4 mg/dl, however, was inconsistent with prerenal azotemia and its coexistence with hyponatremia was suggestive of SIADH or renal salt wasting. 4-6 The patient was, therefore, included in an IRB-approved protocol to differentiate SIADH from renal salt wasting. After obtaining an informed consent, a blood volume study was performed, using a radioisotope dilution technique.7 With a hematocrit of 31%, the red cell volume was decreased by 28% and the plasma volume increased by 4.7%, resulting in a net blood volume reduction of 7.1%. The pertinent baseline laboratory data are summarized in Table 1. The baseline plasma renin, aldosterone, antidiuretic hormone (ADH), and fractional urate excretion were elevated at 8.63ng/ml/h, 16.5ng/dl, 2.5pg/ml, and 29.6% (normal 5-10%), respectively. Plasma osmolality was decreased at 260 mosm/kgH 2 O, atrial natriuretic peptide was in the low normal range at 35 pg/ml, serum phosphorus and urate were decreased at 2.4 and 3.4 mg/dl, respectively. Renal, adrenal, and thyroid functions were normal. The chest X-ray and urinalysis were normal. Saline was then infused at 125 ml/h for 48 h. Urine osmolality of all spontaneously voided urine was immediately determined and when her urine osmolality decreased to 152 mosM/kgH 2 O at 13.3h, a repeat plasma ADH was undetectable when the serum osmolality was 268 mosm/kgH 2 O. At this time, she had received 1660 ml of saline overnight and excreted 955 ml of urine. The plasma renin and aldosterone decreased to 2.95 ng/ml/h and 7.6ng/dl, respectively, and plasma atrial natriuretic peptide increased to a high normal 65 pg/ml. The serum Na remained unchanged at 129mmol/l but the serum urate decreased from 3.4 to 1.7 mg/dl. It should be noted that the baseline urine osmolality of 321 mosm/kgH 2 O increased to 587 mosm/kgH 2 O and the UNa only increased from a baseline of 6 to 18 mmol/l in the first urine passed 4 h after initiation of saline infusion (Figure 1, Table 2). The serum Na gradually increased from 129 to 138 mmol/l at 45.8 h (Figure 2), as serum urate decreased to 1.0 mg/dl and fractional urate excretion remained elevated (Figure 2). Her UNa increased to a peak of 82 mmol/l at 8.1 h (Table 2).

Hypouricemic Action of Selected Flavonoids in Mice: Structure-Activity Relationships

Hyperuricemia and gout appear to be rapidly increasing worldwide and frequently cause symptoms of metabolic syndrome. Dietary flavonoids have their potential beneficial effects on human health. In the present study, 15 flavonoids (quercetin, morin, myricetin, kaempferol, icariin, apigenin, luteolin, baicalin, silibinin, naringenin, formonoetin, genistein, puerarin, daidzin and naringin dihydrochalcone) were selected to investigate for their hypouricemic action in mice. Oral administration of quercetin, morin, myricetin, kaempferol, apigenin and puerarin at 50 and 100 mg/kg for 3 d was able to elicit hypouricemic actions in hyperuricemic mice induced by potassium oxonate. Luteolin, formonoetin and naringenin showed the significant effects only at 100 mg/kg. Quercetin, puerarin, myricetin, morin and kaempferol significantly reduced liver uric acid level in hyperuricemic animals. In addition, quercetin, morin, myricetin, kaempferol and puerarin exhibited significant inhibition on the liver xanthine oxidase (XOD) activities. It seems to be likely that these flavonoids reduce serum urate levels by mainly inhibiting XOD activity. However, the hypouricemic effect of apigenin observed seemed not to parallel with the changes in liver uric acid level and liver XOD activity, implying that apigenin might act via other mechanisms apart from inhibiting enzyme activity simply. Analysis of the chemical structure showed that a planar structure with the hydroxyl groups played a crucial role in hypouricemic activity of flavonoids. The exact mechanism of the hypouricemic action of flavonoids in vivo should be investigated in the future.

Les avancées dans la compréhension des métabolismes protéique et énergétique

To investigate if the gout-protective effect of low-fat dairy products could be attributed to the urate-lowering effect of calcium.This is a placebo-controlled trial in which thirty-five adult (aged 18–42 years) female low-calcium consumers (<800 mg/d) were randomized to one of three treatment groups: low calcium breakfast (control, ∼70 mg of calcium/d) –C or high-calcium breakfast (∼770 mg/d) from calcium citrate – CIT or from skim milk – SM, during 45 consecutive days. Breakfasts were matched for potential confounders and were provided as part of an energy-restricted normoprotein diet containing an additional 800 mg of calcium/d. Dual-energy X-ray absorptiometry measurements (body fat assessment) and fasting blood samples (urate, ionic calcium, PTH, and 1,25-(OH)2-D3) were taken at baseline and the end of the experiment. Clinical trial registration: http://www.ensaiosclinicos.gov.br/ (RBR-7Q2N33).Despite no significant changes in total body weight/fat, CIT and SM led to a significant reduction in serum urate and ionic calcium, but did not affect PTH and vitamin D concentrations compared to C. CIT and SM reduced baseline serum urate by ∼14% and ∼17%, respectively. There was a trend to a positive correlation between changes in serum urate and changes in ionic calcium on day 45 (r = 0.327, P = 0.055).Calcium supplementation (770 mg/d from dairy or calcium citrate) reduced serum urate concentrations, suggesting that the gout-protective effect of low-fat dairy consumption is at least partly due to a urate-lowering effect of calcium.

Febuxostat: a safe and effective therapy for hyperuricemia and gout

Febuxostat is a novel, nonpurine, selective xanthine oxidase inhibitor and is a potential alternative to allopurinol for patients with hyperuricemia and gout. Unlike allopurinol, which undergoes renal elimination, febuxostat is metabolized via hepatic conjugation and oxidation. Phase III studies have shown that febuxostat, at a once-daily dose of 80, 120 or 240 mg (safety dose), is more effective than allopurinol (300 mg) in reducing and maintaining serum urate concentrations lower than 6 mg/dl. Reductions in gout flares and tophus areas with febuxostat treatment are similar to those occurring with allopurinol therapy. Patients with moderate renal impairment can achieve significant serum urate reductions, without dose adjustments. Therefore, febuxostat represents a viable treatment choice, with documented efficacy and safety in hyperuricemia and gout.

Dietary Factors and Hyperuricaemia

The connection of gout and hyperuricaemia with gluttony, overindulgence in food and alcohol and obesity dates from ancient times. Studies from different parts of the world suggest that the incidence and severity of hyperuricaemia and gout may be increasing. Uric acid (urate) is the end product of purine degradation. Although most uric acid is derived from the metabolism of endogenous purine, eating foods rich in purines contributes to the total pool of uric acid. Sustained hyperuricaemia is a risk factor for acute gouty arthritis, chronic tophaceous gout, renal stones and possibly cardiovascular events and mortality. Before starting lifelong urate-lowering drug therapy, it is important to identify and treat underlying disorders that may be contributing to hyperuricaemia. It is relevant to recognize the strong association of the insulin resistance syndrome (IRS) (abdominal obesity, dyslipidaemia, hypertension, raised serum insulin levels and glucose intolerance) with hyperuricaemia. Consumption of meat, seafood and alcoholic beverages in moderation and attention to food portion size is important. Moderation in the consumption of not only beer but also other forms of alcohol is essential. In the obese, controlled weight management has the potential to lower serum urate in a quantitatively similar way to relatively unpalatable "low purine" diets. Non-fat milk and low-fat yogurt have a variety of health benefits and dairy products may have clinically meaningful antihyperuricaemic effects. In addition, fruits, such as cherries and high intakes of vegetable protein diet may reduce serum urate levels.

Febuxostat (TMX‐67), a Novel, Non‐Purine, Selective Inhibitor of Xanthine Oxidase, Is Safe and Decreases Serum Urate in Healthy Volunteers

AbstractFor Abstract see ChemInform Abstract in Full Text.

Y-700, a Novel Inhibitor of Xanthine Oxidase, Suppresses the Development of Colon Aberrant Crypt Foci and Cell Proliferation in 1,2-Dimethylhydrazine-Treated Mice

Y-700, 1-[3-cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid, is a newly synthesized inhibitor of xanthine oxidase. This study found that feeding of Y-700 suppressed the development of colonic aberrant crypt foci, precursor lesions of colon cancer, and cell proliferation in 1,2-dimethylhydrazine-treated mice, accompanied by reduced serum urate. These results suggest that Y-700 is a useful agent for the prevention of colon tumorigenesis and that xanthine oxidase plays an important role in the development of colon cancer.

Gout in Solid Organ Transplantation

Hyperuricaemia occurs in 5-84% and gout in 1.7-28% of recipients of solid organ transplants. Gout may be severe and crippling, and may hinder the improved quality of life gained through organ transplantation. Risk factors for gout in the general population include hyperuricaemia, obesity, weight gain, hypertension and diuretic use. In transplant recipients, therapy with ciclosporin (cyclosporin) is an additional risk factor. Hyperuricaemia is recognised as an independent risk factor for cardiovascular disease; however, whether anti-hyperuricaemic therapy reduces cardiovascular events remains to be determined. Dietary advice is important in the management of gout and patients should be educated to partake in a low-calorie diet with moderate carbohydrate restriction and increased proportional intake of protein and unsaturated fat. While gout is curable, its pharmacological management in transplant recipients is complicated by the risk of adverse effects and potentially severe interactions between immunosuppressive and hypouricaemic drugs. NSAIDs, colchicine and corticosteroids may be used to treat acute gouty attacks. NSAIDs have effects on renal haemodynamics, and must be used with caution and with close monitoring of renal function. Colchicine myotoxicty is of particular concern in transplant recipients with renal impairment or when used in combination with ciclosporin. Long-term urate-lowering therapy is required to promote dissolution of uric acid crystals, thereby preventing recurrent attacks of gout. Allopurinol should be used with caution because of its interaction with azathioprine, which results in bone marrow suppression. Substitution of mycophenylate mofetil for azathioprine avoids this interaction. Uricosuric agents, such as probenecid, are ineffective in patients with renal impairment. The exception is benzbromarone, which is effective in those with a creatinine clearance >25 mL/min. Benzbromarone is indicated in allopurinol-intolerant patients with renal failure, solid organ transplant or tophaceous/polyarticular gout. Monitoring for hepatotoxicty is essential for patients taking benzbromarone. Physicians should carefully consider therapeutic options for the management of hypertension and hyperlipidaemia, which are common in transplant recipients. While loop and thiazide diuretics increase serum urate, amlodipine and losartan have the same antihypertensive effect with the additional benefit of lowering serum urate. Atorvastatin, but not simvastatin, may lower uric acid, and while fenofibrate may reduce serum urate it has been associated with a decline in renal function. Gout in solid organ transplantation is an increasing and challenging clinical problem; it impacts adversely on patients' quality of life. Recognition and, if possible, alleviation of risk factors, prompt treatment of acute attacks and early introduction of hypouricaemic therapy with careful monitoring are the keys to successful management.

Febuxostat (TMX‐67), a Novel, Non‐Purine, Selective Inhibitor of Xanthine Oxidase, Is Safe and Decreases Serum Urate in Healthy Volunteers

In order to evaluate the safety, pharmacological properties, and urate‐lowering efficacy of febuxostat, a non‐purine, selective inhibitor of xanthine oxidase, a Phase 1, 2‐week, multiple‐dose, placebo‐controlled, dose‐escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self‐limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.

A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy.

To evaluate the proposed relationship between persistent reduction of serum urate into the subsaturating range and reduction in the frequency of acute gouty attacks. We retrospectively examined data derived from 267 patients who had experienced at least 1 gouty attack before their first visit to our clinic. Serum urate concentration, history of recurrent gouty attacks, and information about antihyperuricemic drug use were collected on each visit for up to 3 years from the first visit of each patient. Data derived from visits >1 year after study entry were subjected to statistical analysis. When adjusted for baseline serum urate level and the number of gouty attacks prior to study entry, reduction of followup serum urate concentration and antihyperuricemic drug use were each significantly associated with a reduced risk of gouty attacks (odds ratio [OR] 0.42, 95% confidence interval [95% CI] 0.31-0.57; OR 0.22, 95% CI 0.10-0.47, respectively). The data indicate that reduction of serum urate concentrations to 6 mg/dl or lower will eventually result in a reduced frequency or prevention of future gouty attacks.

The effect of short-term treatment with simvastatin on renal function in patients with peripheral arterial disease.

The objective of this study was to investigate the effects of lipid-lowering treatment on renal function in patients with peripheral arterial disease (PAD). This was a retrospective study of hyperlipidemic claudicants referred to a vascular surgery and risk modification clinic. Serum creatinine and urate concentrations and the fasting lipid profile were measured pretreatment and after 3-4 months of treatment with 20 mg/day simvastatin. In 103 consecutive patients with PAD (57 men; 46 women), median age 67 years (range: 51 to 83) there was a significant decrease in serum creatinine from a mean (SD) of 87 (12) micromol/L pretreatment to 84 (12) micromol/L post-treatment (p<0.0001). This difference was more marked in the tertile of patients with the highest baseline creatinine levels. There was also a significant reduction in serum urate from 0.37 (0.07) mmol/L to 0.35 (0.07) mmol/L (p<0.0001). Both these effects were independent of the degree of total cholesterol (TC) or low-density lipoprotein (LDL) cholesterol reduction. There was a significant reduction in TC from 6.6 (1.0) to 5.2 (0.8) mmol/L and LDL cholesterol from 4.3 (1.0) to 2.8 (0.7) mmol/L; both p<0.0001. Significant improvement also occurred in the high-density lipoprotein cholesterol and triglyceride levels. Cholesterol lowering with simvastatin 20 mg/day improved indices of renal function after 3-4 months of treatment in hyperlipidemic patients with PAD. Further studies are needed to establish and define the clinical relevance of these findings, especially in patients with different degrees of renal failure.

Influence of Leflunomide on Renal Handling of Urate and Phosphate in Patients with Rheumatoid Arthritis

Reduction of serum urate and phosphate levels has been observed in patients receiving leflunomide therapy, but the mechanism for such changes has not been evaluated. Thirty-eight patients with rheumatoid arthritis who began leflunomide were studied. Serum urate, creatinine, and phosphate, and 24-hour uric acid, creatinine, and phosphate were measured before, during, and in some instances after leflunomide treatment. Clearances of urate and creatinine, fractional excretion of urate, and tubular reabsorption of phosphate were calculated. Undissociated urinary uric acid was estimated with a nomogram. Twelve patients gave consent to withdraw leflunomide treatment of a 2-week period and underwent a third study. Decreases in serum urate and phosphate levels were observed, with parallel increases in clearances of urate and in fractional excretion of urate, and a reduction in tubular reabsorption of phosphate. Clearances of creatinine and undissociated urinary uric acid remained unchanged. Two weeks after withdrawing the drug, a partial return toward baseline values was observed, but residual changes were apparent. No case of clinical gout was observed. Leflunomide enhances urate and phosphate loss, an effect that partially persisted after 2-week withdrawal. The long-term effect of mild phosphate wasting warrants further investigation. The urate-lowering effect of leflunomide may be useful in monitoring compliance in leflunomide therapy.

Clinical manifestations of gout and their management

Gout is an inflammatory response to deposition of monosodium urate crystals in and around joints. It is primarily a disease of adult men. In acute gout, treatment options include non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids, administered either intra-articularly, orally or parenterally. Asymptomatic hyperuricaemia does not require specific treatment, but should prompt screening for atherosclerosis risk factors, and general lifestyle modification to reduce serum urate levels. Gout presents differently in the elderly. Both women and men are affected, attacks are frequently polyarticular and in the upper limbs, and the gout may be associated with diuretic use, hypertension and renal impairment. In patients with peptic ulcer disease, selective COX-2 inhibitors provide another treatment option. In the presence of renal impairment, allopurinol is the treatment of choice for urate lowering therapy, but doses of allopurinol and colchicine must be adjusted. Urate lowering therapy should only be used if recurrent episodes of gout occur despite aggressive attempts to reverse or control the underlying causes. It should not be introduced or discontinued during an acute episode of gout, and gout prophylaxis (NSAIDs or colchicine) should be prescribed during the introduction of urate lowering therapy.

Treatment of Chronic Gout in Patients with Renal Function Impairment An Open, Randomized, Actively Controlled Study

Treatment of gout and hyperuricemia can be difficult in patients with chronic renal failure. At present, there is no study available comparing the efficacy of the most widely used agent, allopurinol, and the uricosuric benzbromarone for the control of hyperuricemia in patients with renal insufficiency. We describe an open, randomized, actively controlled, comparative trial in patients with clearance of creatinine from 20 to 80 mL/ min/1.73 m(2). Patients were randomized to take benzbromarone (100-200 mg/day) or allopurinol (100-300 mg/day). Outcome variables were the following: reduction of serum urate (Sur), Sur & tl; 6 mg/dL (357 micromol/L), reduction of gouty bouts and reduction of tophi. During 9-24 months of follow-up 36 patients were studied.The reduction of Sur was higher with benzbromarone, and only 1 of 17 patients taking benzbromarone did not achieve Sur < 6 mg/dL versus 7 of 19 taking allopurinol. Patients who did not reach optimal Sur levels with allopurinol were more frequently taking diuretics and showed lower fractional excretion of urate and higher initial Sur levels than patients with proper control of Sur. Seven patients with suboptimal control of serum urate were changed to benzbromarone 100 mg/day, which showed efficacy similar in those who were initially randomized to benzbromarone. A reduction of gouty bouts and size of tophi was observed after proper control of Sur. Allopurinol is effective in controlling hyperuricemia, but patients with higher initial Sur levels or taking concomitant diuretic therapy are less prone to reach therapeutic goals.Benzbromarone is useful for the control of hyperuricemia in patients with renal insufficiency even with concomitant diuretic administration; patients benefited include those who previously had no improvement by taking allopurinol.

Severe debilitating polyarticular gout and terminal renal failure in an allopurinol non-responder

Gout is the most common cause of inflammatory arthritis in men aged more than 50, affecting approximately 1–2% of adult men in the Western world. The incidence and prevalence of gout is on the rise. Increasing longevity, dietary trends, obesity, metabolic syndrome, hypertension, increased use of low-dose aspirin, major organ transplantation and increased survival from coronary artery disease and end-stage renal disease have been implicated as the possible contributory factors. By far, the commonest cause of hyperuricaemia (that accounts for 90% of patients with gout) is decreased renal clearance. Patients with gout should avoid excess of alcohol (beer and spirits, particularly), red-meat and sea-food. Vegetarian food and dairy products reduce the risk of gouty arthritis. For the treatment of acute gout, options include non-steroidal antirheumatic drugs (NSAIDs), steroids (systemic or intra-articular) and colchicine. High dose of colchicine often results in diarrhoea and should be best avoided. Most patients respond within 18 hours to a dose of 0.5 mg twice daily. Colchicine is contraindicated if creatinine clearance is lower than 30 ml/min. Optimal treatment of chronic gout requires long-term reduction of serum urate to the lower half of the normal uric acid reference range. Prevention of attacks requires modification of lifestyle factors such as weight loss, moderation in the consumption of alcohol and meat and withdrawal of drugs known to cause elevated uric acid levels. Drugs used for chronic gout can be divided in three categories: (a) Uricostatic (xanthine oxidase inhibitor), e.g. allopurinol, oxipurinol, febuxostat, (b) Uricosuric, e.g. benzbromarone, sulfinpyrazone, probenecid, losartan, fenofibrate and (c) Uricolytic, e.g. uricozyme, rasburicase. Febuxostat is a new oral xanthine oxidase inhibitor, which has been shown to be more powerful in lowering uric acid levels compared to allopurinol. The drug is mainly metabolised by the liver and can be used in renal and hepatic insufficiency with no dose adjustment. Benzbromarone is an excellent uricosuric agent. Pegylated uricase is currently under development.

Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees

The hypouricemic effect of a newly synthesized xanthine oxidase / xanthine dehydrogenase inhibitor, TEI-6720, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, was investigated and compared with that of allopurinol in male chimpanzees ( n = 3). When allopurinol (10 mg/kg) was administered orally once a day for three consecutive days, it cumulatively reduced serum urate levels by 29.7, 50.1 and 60.2%, 24, 48 and 72 h, respectively, after the initial dose. This effect was dose dependent at doses of 3 and 10 mg/kg. At 3 mg/kg, the mean serum urate levels were 3.1, 2.4, 2.5 and 2.3 mg/dl before and 24, 48 and 72 h, respectively, after the initial dose. Animals treated with 10 mg/kg of allopurinol showed serum urate levels of 3.3, 2.3, 1.6 and 1.3 mg/dl, respectively. The urate-lowering effect of TEI-6720 was then comapred with that of allopurinol at a daily dose of 5 mg/kg ( n = 3). Both compounds caused striking reductions in serum and urinary uric acid levels accompanied by an increase in urinary xanthine levels. These effects of TEI-6720 were more potent than those of allopurinol. TEI-6720 reduced serum urate levels by 55.9, 69.6 and 73.6%, 24, 48 and 72 h, respectively, after the first dose, whereas, the corresponding values after allopurinol were 28.1, 41.6 and 45.1%. These results suggest that the hypouricemic effect of TEI-6720 may be more potent than that of allopurinol in the treatment of hyperuricemia and gout, and that TEI-6720 may become an effective alternative drug.

Potomac Horse fever now in Western Canada

Sodium glucose co-transporter 2 inhibitors have been shown to reduce serum urate concentration. The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program integrated data from two similarly designed, randomised, double-blind, placebo-controlled trials (CANVAS and CANVAS-Renal) assessing the cardiovascular and renal safety of canagliflozin compared with placebo in patients with type 2 diabetes. In this post-hoc analysis, we aimed to investigate the effect of canagliflozin compared with placebo on gout in the CANVAS Program.In the CANVAS Program, individuals with type 2 diabetes and an elevated risk of cardiovascular disease were randomly assigned to receive either canagliflozin (100 or 300 mg) or placebo. In this post-hoc analysis, we assessed the effects of canagliflozin versus placebo on serum urate concentration using mixed linear models and the occurrence of either an adverse event attributed to gout flare or the commencement of a drug for gout using Kaplan-Meier analysis with Cox proportional hazards models to determine a hazard ratio (HR) and 95% CIs. All analyses were done according to the principle of intention to treat, and there was no imputation for missing data.10 142 participants were included in analyses. At baseline, mean age was 63 years (SD 8), 3633 (36%) participants were female, mean serum urate concentration was 348·9 μmol/L (95·5), and 471 (5%) of participants had a history of gout. Mean follow-up was 3·6 years (SD 2·0) and mean serum urate concentration was −23·3 μmol/L (95% CI −25·4 to −21·3) lower in participants treated with canagliflozin than in those who received placebo, equating to a 6·7% reduction in serum urate (percentage difference −6·7%, 95% CI −7·3 to −6·1). During follow-up, 80 individuals reported an episode of gout flare and 147 commenced a drug for gout. The occurrence of gout flare or the need for treatment for gout was lower in participants treated with canagliflozin than in those who received placebo (HR 0·53, 95% CI 0·40–0·71; p<0·0001). The proportional reduction for gout flare adverse events (2·0 patients with an event per 1000 patient-years in the canagliflozin group vs 2·6 patients with an event per 1000 patient-years in the placebo group; 0·64, 95% CI 0·41–0·99; p=0·046) was similar in size to that for commencement of a drug for gout (3·3 vs 5·4 patients with an event per 1000 patient-years; 0·52, 0·38–0·72; p<0·0001) and hyperuricaemia (1·8 vs 2·5 patients with an event per 1000 patient-years; 0·59, 0·37–0·93; p=0·023).In this post-hoc analysis, compared with placebo, canagliflozin reduced serum urate concentration and also reduced events related to gout flare among patients with type 2 diabetes. A trial explicitly designed to test the effects of sodium glucose co-transporter 2 inhibition on gout is required to confirm these observations.Janssen Research & Development.