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1.  Can racial disparities in optimal gout treatment be reduced? evidence from a randomized trial 
BMC Medicine  2012;10:15.
There is a disproportionate burden of gout in African-Americans in the U.S. due to a higher disease prevalence and lower likelihood of receiving urate-lowering therapy (ULT), compared to Caucasians. There is an absence of strong data as to whether the response to ULT differs by race/ethnicity. BMC Musculoskeletal Disorders recently published a secondary analyses of the CONFIRMS trial, a large randomized controlled, double-blind trial of 2,269 gout patients. The authors reported that the likelihood of achieving the primary study efficacy end-point of achieving serum urate < 6 mg/dl was similar between African-Americans and Caucasians, for all three treatment arms (Febuxostat 40 mg and 80 mg and allopurinol 300/200 mg). More importantly, rates were similar in subgroups of patients with mild or moderate renal insufficiency. Adverse event rates were similar, as were the rates of gout flares. These findings constitute a convincing evidence to pursue aggressive ULT in gout patients, regardless of race/ethnicity. This approach will likely help to narrow the documented racial disparities in gout care.
Please see related article: http://www.biomedcentral.com/1471-2474/13/15
doi:10.1186/1741-7015-10-15
PMCID: PMC3337326  PMID: 22316088
Gout; Disparity; Race; treatment; Febuxostat; Allopurinol; randomized; African-American
2.  The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial 
Introduction
The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial.
Methods
Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.
Results
Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group.
Conclusions
Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable.
Clinical Trial Registration
NCT00430248
doi:10.1186/ar2978
PMCID: PMC2888216  PMID: 20370912
3.  Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout 
Core evidence  2010;4:25-36.
Introduction:
Gout is a common and disabling cause of arthritis in middle-aged and elderly populations, with its main predisposing factor being hyperuricemia (serum urate > 6.8 mg/dL). Options for treatment of chronic gout until 2008 were allopurinol, a xanthine oxidase inhibitor, and the group of drugs known as uricosurics that stimulate the renal excretion of uric acid. A proportion of patients, including some with chronic kidney disease and solid organ transplantations, could not be treated with the those therapies because of intolerance, drug interactions, or adverse events. Febuxostat is a nonpurine xanthine oxidase inhibitor, recently approved in Europe and the United States for the treatment of chronic gout.
Aim:
To review the clinical evidence (phase II and III studies) of the effectiveness and safety of febuxostat for treatment of hyperuricemia and gout.
Evidence review:
Febuxostat, at doses ranging from 40 to 240 mg/day, is efficacious in reducing serum urate in patients with hyperuricemia and gout, comparing favorably with fixed doses of allopurinol in that respect. Early safety signals with respect to liver test abnormalities and cardiovascular outcomes have not been confirmed in recent large prospective trials but need to be further monitored.
Clinical potential:
Given its low cost and extensive clinical experience, allopurinol will likely remain the first-line drug for management of hyperuricemia and gout. Febuxostat may provide an important option in patients unable to use allopurinol, those with very high serum urate levels, or in the presence of refractory tophi.
PMCID: PMC2899777  PMID: 20694062
febuxostat; gout; hyperuricemia; evidence
4.  African American patients with gout: efficacy and safety of febuxostat vs allopurinol 
Background
African Americans are twice as likely as Caucasians to develop gout, but they are less likely to be treated with urate-lowering therapy (ULT). Furthermore, African Americans typically present with more comorbidities associated with gout, such as hypertension, obesity, and renal impairment. We determined the efficacy and safety of ULT with febuxostat or allopurinol in African American subjects with gout and associated comorbidities and in comparison to Caucasian gout subjects.
Methods
This is a secondary analysis of the 6-month Phase 3 CONFIRMS trial. Eligible gouty subjects with baseline serum urate (sUA) ≥ 8.0 mg/dL were randomized 1:1:1 to receive febuxostat 40 mg, febuxostat 80 mg, or allopurinol (300 mg or 200 mg depending on renal function) daily. All subjects received gout flare prophylaxis. Primary efficacy endpoint was the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the final visit. Additional endpoints included the proportion of subjects with mild or with moderate renal impairment who achieved a target sUA < 6.0 mg/dL at final visit. Adverse events (AEs) were recorded throughout the study.
Results
Of the 2,269 subjects enrolled, 10.0% were African American and 82.1% were Caucasian. African American subjects were mostly male (89.5%), obese (BMI ≥ 30 kg/m2; 67.1%), with mean baseline sUA of 9.8 mg/dL and mean duration of gout of 10.4 years. The proportions of African American subjects with a baseline history of diabetes, renal impairment, or cardiovascular disease were significantly higher compared to Caucasians (p < 0.001). ULT with febuxostat 80 mg was superior to both febuxostat 40 mg (p < 0.001) and allopurinol (p = 0.004). Febuxostat 40 mg was comparable in efficacy to allopurinol. Significantly more African American subjects with mild or moderate renal impairment achieved sUA < 6.0 mg/dL in the febuxostat 80 group than in either the febuxostat 40 mg or allopurinol group (p < 0.05). Efficacy rates in all treatment groups regardless of renal function were comparable between African American and Caucasian subjects, as were AE rates.
Conclusions
In African American subjects with significant comorbidities, febuxostat 80 mg is significantly more efficacious than either febuxostat 40 mg or allopurinol 200/300 mg. Febuxostat was well tolerated in this African American population.
Please see related article: http://www.biomedcentral.com/1741-7015/10/15
doi:10.1186/1471-2474-13-15
PMCID: PMC3317813  PMID: 22316106
5.  Febuxostat in the management of hyperuricemia and chronic gout: a review 
Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insufficiency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout flares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the first major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and efficacy is required.
PMCID: PMC2643102  PMID: 19337428
febuxostat; TEI-6720; TMX-67; gout; hyperuricemia; xanthine oxidase inhibitor
6.  The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age 
BMC Geriatrics  2012;12:11.
Background
The incidence of gout rises with increasing age. Management of elderly (≥65 years) gout patients can be challenging due to high rates of comorbidities, such as renal impairment and cardiovascular disease, and concomitant medication use. However, there is little data specifically addressing the efficacy and safety of available urate-lowering therapies (ULT) in the elderly. The objective of this post hoc analysis was to examine the efficacy and safety of ULT with febuxostat or allopurinol in a subset of elderly subjects enrolled in the CONFIRMS trial.
Methods
Hyperuricemic (serum urate [sUA] levels ≥ 8.0 mg/dL) gout subjects were enrolled in the 6-month, double-blind, randomized, comparative CONFIRMS trial and randomized, 1:1:1, to receive febuxostat, 40 mg or 80 mg, or allopurinol (200 mg or 300 mg based on renal function) once daily. Flare prophylaxis was provided throughout the study duration.
Study endpoints were the percent of elderly subjects with sUA <6.0 mg/dL at the final visit, overall and by renal function status, percent change in sUA from baseline to final visit, flare rates, and rates of adverse events (AEs).
Results
Of 2,269 subjects enrolled, 374 were elderly. Febuxostat 80 mg was significantly more efficacious (82.0%) than febuxostat 40 mg (61.7%; p < 0.001) or allopurinol (47.3%; p < 0.001) for achieving the primary efficacy endpoint. Febuxostat 40 mg was also superior to allopurinol in this population (p = 0.029). In subjects with mild-to-moderate renal impairment, significantly greater ULT efficacy was observed with febuxostat 40 mg (61.6%; p = 0.028) and febuxostat 80 mg (82.5%; p < 0.001) compared to allopurinol 200/300 mg (46.9%). Compared to allopurinol 200/300 mg, the mean percent change in sUA from baseline was significantly greater for both febuxostat 80 mg (p < 0.001) and febuxostat 40 mg (p = 0.011) groups. Flare rates declined steadily in all treatment groups. Rates of AEs were low and comparable across treatments.
Conclusions
These data suggest that either dose of febuxostat is superior to commonly prescribed fixed doses of allopurinol (200/300 mg) in subjects ≥65 years of age with high rates of renal dysfunction. In addition, in this high-risk population, ULT with either drug was well tolerated.
Trial registration
clinicaltrials.gov NCT#00430248
doi:10.1186/1471-2318-12-11
PMCID: PMC3368715  PMID: 22436129
7.  Management of hyperuricemia in gout: focus on febuxostat 
Gout is the most common inflammatory arthritis in an elderly population, and can be diagnosed with absolute certainty by polarization microscopy. However, diagnosis may be challenging because atypical presentations are more common in the elderly. Management of hyperuricemia in the elderly with gout requires special consideration because of co-medication, contra-indications, and risk of adverse reactions. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used sensibly in the elderly, especially when renal function impairment is present. However, if used at the lowest dose that maintains the serum urate level below 5.0 to 6.0 mg/dL (0.30 to 0.36 mmol/L), the excess urate in the body will eventually be eliminated, acute flares will no longer occur, and tophi will resolve. Febuxostat, a new xanthine oxidase inhibitor, is welcomed, as few alternatives for allopurinol are available. Its pharmacokinetics and pharmacodynamics are not significantly altered in patients with moderate renal function or hepatic impairment. Its antihyperuricemic efficacy at 80 to 120 mg/day is better than “standard dosage” allopurinol (300 mg/day). Long-term safety data and efficacy data on tophus diminishment and reduction of gout flares have recently become available. Febuxostat may provide an important option in patients unable to use allopurinol, or refractory to allopurinol.
PMCID: PMC2817937  PMID: 20169038
aging; febuxostat; hyperuricemia; gout; pharmacotherapy; xanthine oxidase
8.  Advances in the management of gout: Critical appraisal of febuxostat in the control of hyperuricemia 
Gout recently passed rheumatoid arthritis to become the most common inflammatory arthritis in the United States (US). However, epidemiologic studies indicate that the quality of gout management is suboptimal owing to both patient and physician issues. Only three options for urate-lowering therapy are currently available in the US: allopurinol, probenecid, and recently, febuxostat. Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function. Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels. In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect. Febuxostat is a new medication that may offer several advantages and can be given as an alternative to allopurinol. We review the basic biology and clinical performance of febuxostat, and consider the potential utility of this agent in comparison to the older, better-established gout therapeutics.
PMCID: PMC3108781  PMID: 21694922
allopurinol; gout suppressants; nephrolithiasis; uric acid; urolithiasis
9.  Long-Term Inhibition of Xanthine Oxidase by Febuxostat Does Not Decrease Blood Pressure in Deoxycorticosterone Acetate (DOCA)-Salt Hypertensive Rats 
PLoS ONE  2013;8(2):e56046.
Xanthine oxidase and its products, uric acid and ROS, have been implicated in the pathogenesis of cardiovascular disease, such as hypertension. We have previously reported that allopurinol inhibition of XO does not alter the progression of deoxycorticosterone acetate (DOCA)-salt hypertension in rats. However other researchers have observed a reduction in blood pressure after allopurinol treatment in the same model. To resolve this controversy, in this study we used the newer and more effective XO inhibitor febuxostat, and hypothesized that a more complete XO blockade might impair hypertension development and its end-organ consequences. We used DOCA-salt hypertensive rats and administered vehicle (salt water) or febuxostat (orally, 5 mg/kg/day in salt water) in a short-term “reversal” experiment (2 weeks of treatment 3 weeks after DOCA-salt beginning) and a long-term “prevention” experiment (treatment throughout 4 weeks of DOCA-salt). We confirmed XO inhibition by febuxostat by measuring circulating and tissue levels of XO metabolites. We found an overall increase in hypoxanthine (XO substrate) and decrease in uric acid (XO product) levels following febuxostat treatment. However, despite a trend for reduced blood pressure in the last week of long-term febuxostat treatment, no statistically significant difference in hemodynamic parameters was observed in either study. Additionally, no change was observed in relative heart and kidney weight. Aortic media/lumen ratio was minimally improved by long-term febuxostat treatment. Additionally, febuxostat incubation in vitro did not modify contraction of aorta or vena cava to norepinephrine, angiotensin II or endothelin-1. We conclude that XO inhibition is insufficient to attenuate hypertension in the rat DOCA-salt model, although beneficial vascular effects are possible.
doi:10.1371/journal.pone.0056046
PMCID: PMC3564945  PMID: 23393607
10.  Febuxostat: A Novel Agent for Management of Hyperuricemia in Gout 
Gout is a metabolic disorder characterized by elevated uric acid levels in the body, associated with painful arthritis, tophi and nephropathy. The most frequently used pharmacologic urate lowering strategies involve reducing urate production with a xanthine oxidase inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. Urate lowering agents are limited in number, availability and effectiveness. The emergence of a new medication, febuxostat, to lower serum urate levels is welcome as no new drug have been approved since the introduction of allopurinol, in 1964, and the drugs that are available have limitations owing to inefficacy or toxicity. Febuxostat is a novel, nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout.
doi:10.4103/0250-474X.100231
PMCID: PMC3480742  PMID: 23112391
Gout; hyperuricemia; xanthine oxidase inhibitor
11.  New and improved strategies for the treatment of gout 
The Western world appears to be in the midst of the third great gout epidemic of all time. In this century, gout is increasing in prevalence despite an increased understanding of its risk factors and pathophysiology, and the availability of reasonably effective treatment. The main cultural factors responsible for this appear to be diet, obesity, ethanol use and medications. Excess fructose consumption is a newly recognized modifiable risk factor. The debate has been renewed concerning hyperuricemia as an independent risk factor for renal insufficiency and cardiovascular disease. Prevention is still rooted in lifestyle choices. Existing treatments have proven to be unsatisfactory in many patients with comorbidities. New treatments are available today and on the horizon for tomorrow, which offer a better quality of life for gout sufferers. These include febuxostat, a nonpurine inhibitor of xanthine oxidase with a potentially better combination of efficacy and safety than allopurinol, and investigational inhibitors of URAT-1, an anion exchanger in the proximal tubule that is critical for uric acid homeostasis. New abortive treatments include interleukin-1 antagonists that can cut short the acute attack in 1 to 2 days in persons who cannot take nonsteroidal anti-inflammatory drugs, colchicine or corticosteroids. Lastly, newer formulations of uricase have the ability to dissolve destructive tophi over weeks or months in patients who cannot use currently available hypouricemic agents. Diagnostically, ultrasound and magnetic resonance imaging offer advanced ways to diagnose gout noninvasively, and just as importantly, a way to follow the progress of tophus dissolution. The close association of hyperuricemia with metabolic syndrome, hypertension and renal insufficiency ensures that nephrologists will see increasing numbers of gout-afflicted patients.
doi:10.2147/IJNRD.S6048
PMCID: PMC3108771  PMID: 21694941
hyperuricemia; metabolic syndrome; tophi; colchicine; febuxostat; allopurinol
12.  Tophaceous Gout and Renal Insufficiency: A New Solution for an Old Therapeutic Dilemma 
Case Reports in Medicine  2011;2011:397646.
The prevalence of gout is increasing with increased life expectancy. Approximately half of the patients with gout have some degree of renal impairment. If both conditions persistently coexist, and in severe tophaceous gout, in particular, treatment has been difficult. We here report on the case of an 87-year-old woman, who had been suffering from recurrent gouty arthritis over 4 years. Monthly polyarthritis attacks were accompanied by subcutaneous tophi. Serum uric acid levels were constantly above 600 μmol/L (10 mg/dL). Allopurinol was no option because of intolerance, while benzbromarone was ineffective because of renal impairment. Therefore, the novel xanthin oxidase inhibitor febuxostat was started, achieving rapid control of serum urate levels (<360 μmol/L). After initial worsening of inflammation in the first weeks, gouty attacks stopped and all tophi resolved within the following 10 months. Renal function remained stable.
doi:10.1155/2011/397646
PMCID: PMC3099210  PMID: 21629805
13.  Evaluation of effect of allopurinol and febuxostat in behavioral model of depression in mice 
Indian Journal of Pharmacology  2013;45(3):244-247.
Objective:
To evaluate the effects of allopurinol and febuxostat on depression using Forced Swim Test (FST) in mice.
Materials and Methods:
Allopurinol (39 mg/kg p. o) and febuxostat (15.6 mg/kg p. o) were administered once daily for 21 successive days to Swiss Albino mice. On the 21st day, the effect of the drug on locomotion was tested using photo-actometer followed by the recording of immobility period in the FST and the results were compared with the standard drug fluoxetine (10 mg/kg p. o).
Results:
Allopurinol and febuxostat expressed significant antidepressant like effect as indicated by reduction in the immobility period of mice in the FST as compared to control group. The effects of allopurinol and febuxostat were found to be comparable to that of fluoxetine.
Conclusion:
The results of the present study indicate that allopurinol and febuxostat possess significant antidepressant like activity.
doi:10.4103/0253-7613.111922
PMCID: PMC3696294  PMID: 23833366
Forced swim test; photo-actometer; serotonin; tryptophan
14.  Pegloticase for Treatment of Tophaceous Polyarticular Gout 
This is a case report of a patient with treatment resistant gout who was prescribed pegloticase and developed a severe reaction. A 30-year-old Hawaiian-Filipino man presented with a nine-year history of gout that progressed from episodic monoarticular arthritis, treated with aspiration and corticosteroid injections, to more aggressive disease with more frequent attacks requiring escalation of therapy. He was treated with systemic corticosteroids, colchicine and nonsteroidal anti-inflammatory drugs, but then required allopurinol. Despite aggressive therapy, the patient continued to have hyperuricemia and tophi developed even after treatment with febuxostat and probenicid. The patient became wheel chair bound due to his pain and, at that point, the decision was made to initiate treatment with pegloticase. The patient initially experienced significant improvement with treatment; however, he soon began to have elevation in his serum uric acid levels and developed a severe reaction during treatment.
PMCID: PMC3727571  PMID: 23901393
pegloticase; tophi; treatment resistant gout; infusion reaction
15.  Diabetes and gout: efficacy and safety of febuxostat and allopurinol 
Diabetes, Obesity & Metabolism  2013;15(11):1049-1055.
Aim Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents.
Methods Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ≥8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial.
Results Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m2) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events.
Conclusions Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses.
doi:10.1111/dom.12135
PMCID: PMC3902994  PMID: 23683134
clinical trial; diabetes mellitus; drug utilisation
16.  DELAYED TREATMENT EFFECTS OF XANTHINE OXIDASE INHIBITION ON SYSTOLIC OVERLOAD-INDUCED LEFT VENTRICULAR HYPERTROPHY AND DYSFUNCTION 
The nonpurine selective xanthine oxidase (XO) inhibitor febuxostat attenuates development of left ventricular (LV) hypertrophy and dysfunction in mice when treatment is initiated within 1 hour of transverse aortic constriction (TAC). This study investigated whether a 7-day delay of treatment with the XO inhibitors febuxostat or allopurinol would reverse TAC-induced changes after onset of heart failure (HF). Neither treatment significantly affected TAC-induced LV hypertrophy; only febuxostat caused a modest improvement in LV function (∼10% increase in LV ejection fraction). However, the purine analog allopurinol tended to increase mortality compared with vehicle or febuxostat in HF mice.
doi:10.1080/15257771003738683
PMCID: PMC2903770  PMID: 20544512
Febuxostat; allopurinol; heart failure; left ventricular dysfunction
17.  Latest evidence on gout management: what the clinician needs to know 
Until recently, the last drug approved for the treatment of gout by the United States Food and Drug Administration was allopurinol in 1966. Since 2008, two new drugs for the treatment of gout, febuxostat and pegloticase, have been approved in the US. Febuxostat has been approved in the EU and pegloticase approval is anticipated. A new single-ingredient colchicine preparation is available in the US, and the treatment recommendations for the use of colchicine in acute gout have evolved, now favoring a low-dose regimen. Several other exciting drugs are in development. Herein, we review some of basic principles in the diagnosis and staging of gout. We then examine current treatment principles, with particular attention to febuxostat and pegloticase, offering suggestions as to where they might fit into a modern therapeutic algorithm for gout treatment. We then present available data on several exciting new agents in development, including interleukin-1 inhibitors, and relate them to advances in our understanding of gout pathogenesis. We conclude with some important nonpharmacologic principles for optimal management of this ancient and eminently treatable disease. Dedicated gout research, going on quietly in the background of other breathtaking advances in rheumatology, is now paying off. This comes at a time when the number of patients affected by gout continues to rise, mainly due to an epidemic of obesity. An effort to improve lifestyle choices as a society and better management of the disease by clinicians should have a positive impact on gout incidence and outcome in our lifetimes.
doi:10.1177/2040622312462056
PMCID: PMC3539261  PMID: 23342241
febuxostat; gout; hyperuricemia; inflammasome; interleukin-1; pegloticase; uric acid
18.  Febuxostat Inhibition of Endothelial-Bound XO: Implications for Targeting Vascular ROS Production 
Free radical biology & medicine  2011;51(1):179-184.
Xanthine oxidase (XO) is a critical source of reactive oxygen species (ROS) that contribute to vascular inflammation. Binding of XO to vascular endothelial cell glycosaminoglycans (GAGs) results in significant resistance to inhibition by traditional pyrazolopyrimidine-based inhibitors such as allopurinol. Therefore, we compared the extent of XO inhibition (free and GAG-bound) by allopurinol to febuxostat, a newly approved nonpurine XO-specific inhibitor. In solution, febuxostat was 1000 fold more potent than allopurinol inhibition of XO-dependent uric acid formation (IC50 = 1.8 nM vs. 2.9 μM). Association of XO with heparin-Sepharose 6B (HS6B-XO) had minimal effect on inhibition of uric acid formation by febuxostat (IC50 = 4.4 nM) while further limiting the effect of allopurinol (IC50 = 64 μM). Kinetic analysis of febuxostat inhibition revealed Ki values of 0.96 nM (free) and 0.92 nM (HS6B-XO), confirming equivalent inhibition for both free and GAG-immobilized enzyme. When XO was bound to endothelial cell GAGs, complete enzyme inhibition was observed with 25 nM febuxostat, while no more than 80% inhibition was seen with either allopurinol or oxypurinol, even at concentrations above those tolerated clinically. The superior potency for inhibition of endothelium-associated XO is predictive of a significant role for febuxostat in investigating pathological states where XO-derived ROS are contributive and traditional XO inhibitors are only slightly effective.
doi:10.1016/j.freeradbiomed.2011.04.004
PMCID: PMC3130629  PMID: 21554948
19.  Efficacy and Safety of Febuxostat in Patients with Hyperuricemia and Gout 
The past decade has witnessed an exponential increase of novel therapeutic modalities for a variety of rheumatic disorders, including gout. During the past few years two novel therapeutic agents have been approved by the US Food and Drug Administration for the treatment of hyperuricemia in patients with gout, one of them being febuxostat, a nonpurine selective inhibitor of xanthine oxidase. Review of its pharmacokinetics and pharmacodynamics, efficacy and safety profile, and use in gout patients with comorbid conditions reveals that age and gender have no clinically significant effect and dose adjustments based on age or gender are not required. In addition, febuxostat can be used in patients with mild-to-moderate renal or hepatic involvement. Its overall efficacy and safety profile is comparable and, in certain subsets such as gout patients with mild and moderate renal insufficiency, is superior to allopurinol.
doi:10.1177/1759720X11416405
PMCID: PMC3383531  PMID: 22870483
hyperuricemia; febuxostat; gout; safety profile; efficacy profile
20.  Developments in the scientific and clinical understanding of gout 
Gout is the most common form of inflammatory arthritis in the elderly. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into the transporters that handle uric acid in the kidney as well as possible links between these transporters, hyperuricemia, and hypertension. The treatment of established hyperuricemia has also seen new developments. Febuxostat and PEG-uricase are two novel treatments that have been evaluated and shown to be highly effective in the management of hyperuricemia, thus enlarging the therapeutic options available to lower uric acid levels. Monosodium urate (MSU) crystals are potent inducers of inflammation. Within the joint, they trigger a local inflammatory reaction, neutrophil recruitment, and the production of pro-inflammatory cytokines as well as other inflammatory mediators. Experimentally, the uptake of MSU crystals by monocytes involves interactions with components of the innate immune system, namely Toll-like receptor (TLR)-2, TLR-4, and CD14. Intracellularly, MSU crystals activate multiple processes that lead to the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome complex that in turn processes pro-interleukin (IL)-1 to yield mature IL-1β, which is then secreted. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances in the understanding of hyperuricemia and gout provide new therapeutic targets for the future.
doi:10.1186/ar2509
PMCID: PMC2592794  PMID: 18947374
21.  Comparative trial of azapropazone and indomethacin plus allopurinol in acute gout and hyperuricaemia 
This study compared the effects of azapropazone and indomethacin plus allopurinol in the management of acute gout and hyperuricaemia. A group of 93 patients predominantly based in general practice were randomly allocated to the two treatment regimens (azapropazone (days 1-225) or indomethacin (1-28) followed by allopurinol (29-225)) on a double-blind double dummy basis. Azapropazone produced a substantial reduction in serum uric acid levels by day 4 compared with day 1 (P<0.002) and was superior to indomethacin with regard to recorded levels of serum uric acid at day 4 (P<0.01) and day 28 (P<0.05). From day 28 onwards allopurinol produced and azapropazone maintained similar reductions in serum uric acid. Both treatments rapidly controlled the initial acute attacks of gout and both produced side effects similar in frequency and nature. Fewer breakthrough attacks of gout occurred in the azapropazone group (12) than the indomethacin/allopurinol group (21).
Although the results achieved in both treatment groups were similar it has been shown that azapropazone is effective monotherapy for controlling both acute attacks of gout and hyperuricaemia.
PMCID: PMC1711162  PMID: 3330140
22.  Effect of Acute Xanthine Oxidase Inhibition on Myocardial Energetics During Basal and Very High Cardiac Workstates 
Myocardial ischemia is associated with reduced myocardial adenosine triphosphate (ATP) and increased free adenosine diphosphate (ADP) similar to the normal heart at very high cardiac workstates (HCW). We examined whether acute xanthine oxidase inhibition (XOI) in vivo can decrease myocardial free ADP in normal hearts functioning at basal cardiac workstates (BCW) or very HCW (catecholamine-induced). Myocardial high-energy phosphate (31P magnetic resonance spectroscopy), blood flow (radioactive microspheres), and oxygen consumption (MVO2) were measured in an open-chest canine model before and after infusion of vehicle or an XO inhibitor (allopurinol or febuxostat; n= 10 in each group) during BCW and infusion of dobutamine + dopamine to induce a very HCW. During BCW, both allopurinol and febuxostat resulted in higher phosphocreatine (PCr)/ATP, corresponding to lower ADP levels. During vehicle infusion, HCW caused a decrease of PCr/ATP and an increase in myocardial free ADP. Although XOI did not prevent an increase in free ADP during catecholamine infusion, the values in the allopurinol or febuxostat groups (0.141±0.012 and 0.136±0.011 μmol/g dry wt, respectively) remained significantly less than in the vehicle group (0.180±0.017; P<0.05). Thus, at a given rate of ATP synthesis, XOI decreased the free ADP level needed to drive ATP synthesis, suggesting a more energy-efficient status. As contractile dysfunction in ischemia is characterized by increase of myocardial free ADP and energy deficiency, the data suggest that XOI might be a potential therapy for improving energy efficiency during myocardial ischemia.
doi:10.1007/s12265-011-9276-0
PMCID: PMC3965326  PMID: 21584861
Myocardial high-energy phosphates; Reactive oxygen species; Magnetic resonance spectroscopy; Allopurinol; Febuxostat
23.  Allopurinol treatment and its effect on renal function in gout: a controlled study. 
Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys.
PMCID: PMC1000865  PMID: 7039523
24.  Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout 
Annals of the Rheumatic Diseases  1998;57(9):545-549.
OBJECTIVES—To study the efficacy of allopurinol and benzbromarone to reduce serum urate concentrations in patients with primary chronic gout.
METHODS—Prospective, parallel, open study of 86 consecutive male patients with primary chronic gout. Forty nine patients (26 normal excretors and 23 under excretors) were given allopurinol 300 mg/day and 37 under excretors benzbromarone 100 mg/day. After achieving steady plasma urate concentrations with such doses, treatment was then adjusted to obtain optimal plasmatic urate concentrations (under 6 mg/dl).
RESULTS—Patients receiving allopurinol 300 mg/day showed a mean reduction of plasmatic urate of 2.75 mg/dl (from 8.60 to 5.85 mg/dl) and 3.34 mg/dl (from 9.10 to 5.76 mg/dl) in normal excretors and under excretors respectively. Patients receiving benzbromarone 100 mg/day achieved a reduction of plasmatic urate of 5.04 mg/dl (from 8.58 to 3.54 mg/dl). Fifty three per cent of patients receiving allopurinol and 100% receiving benzbromarone achieved optimal plasma urate concentrations at such doses. The patients with poor results with allopurinol 300 mg/day achieved a proper plasma urate concentration with allopurinol 450 to 600 mg/day, the mean final dose being 372 mg/day. Renal fuction improved and no case of renal lithiasis was observed among benzbromarone treated patients, whose mean final dose was 76 mg/day.
CONCLUSION—Benzbromarone is very effective to control plasma urate concentrations at doses ranging from 50 to 100 mg/day. Uricosuric treatment is a suitable approach to the treatment of patients with gout who show underexcretion of urate.

 Keywords: gout; gout suppressants; allopurinol; benzbromarone
PMCID: PMC1752740  PMID: 9849314
25.  Pharmacokinetics and pharmacodynamics of febuxostat under fasting conditions in healthy individuals 
The aim of the present study was to investigate the pharmacokinetic and pharmacodynamic characteristics of febuxostat following the administration of single and multiple oral doses under fasting conditions to healthy individuals. Thirty-six healthy subjects were randomly divided into three groups, each containing 12 subjects (six male and six female) as follows: Group A, treated with a single oral dose of febuxostat (40 mg); group B, treated with a single oral dose of febuxostat (80 mg) followed by multiple oral doses of febuxostat for 7 days; and group C, treated with a single oral dose of febuxostat (120 mg). Blood samples were collected, and the plasma drug levels and serum uric acid (UA) concentrations were determined by clinical laboratory testing. Febuxostat displayed a linear pharmacokinetic profile for oral doses of 40 to 120 mg. Drug accumulation was not detected following multiple oral doses. When febuxostat was administered as single doses of 40, 80 and 120 mg, the 24-h UA concentration (UA24) values displayed a linear correlation with the dosage. The relationship between UA24 and the three single dose levels (40, 80 and 120 mg) was analyzed. The difference in UA24 between every single dose was significant (P<0.05). After 3 and 7 days of dosing, reductions of 46.67 and 52.69%, respectively, were observed in UA24. On day 7 of dosing, the mean reduction in the UA concentration was 51.83±7.00%. This study demonstrates that febuxostat reduces serum UA concentrations in a dose-linear manner.
doi:10.3892/etm.2013.1414
PMCID: PMC3881071  PMID: 24396412
febuxostat; pharmacokinetics; pharmacodynamics; serum uric acid

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