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Serum Uric Acid–Lowering Therapies:Where Are We Heading in Management

of Hyperuricemia and the PotentialRole of UricaseJohn S. Bomalaski, MD * and Mike A. Clark, PhD

Address*Medical College of Pennsylvania Hospital, Drexel University Collegeof Medicine, 3300 Henry Avenue, Philadelphia, PA 19129, USA.E-mail: [email protected]

Current Rheumatology Reports 2004, 6:240– 247Current Science Inc. ISSN 1523–3774Copyright © 2004 by Current Science Inc.

IntroductionHyperuricemia is currently in the medical headlines.The increasing incidence of gout and awareness of therelationship between hyperuricemia and vascular sequelaehave re-emphasized the importance of hyperuricemia torheumatologists. Gout is increasing worldwide. In the US,using the Rochester Epidemiology Project at the MayoClinic, a greater than twofold increase in the incidence of primary gout was documented for 1995 to 1996 comparedwith 20 years earlier [1]. This correlated with the increasein gout seen in the UK and New Zealand. Increasesalso have been observed in the Shantou area in China [2].In Taiwan, the age of onset decreased, more femaleswere affected, and an increased association with obesity

and hypertriglyceridemia was found [3], as well as a highprevalence among aborigines [4]. Patients requiring aheart or liver transplantation have increased morbidity and mortality if they are hyperuricemic [5,6]. Elevated

uric acid has been further associated with ischemic stroke, blood pressure elevation, and lipid abnormalities,although the direct toxic effects of hyperuricemia remaincontroversial [7••,8]. Thus, there is increasing interest inhyperuricemia and its management from more medicalspecialties than rheumatology.

During the past year, two excellent reviews on gout appeared [9••,10••]. These studies emphasized thedifficulty in treating patients with hyperuricemia that does not respond to allopurinol or is associated withhypersensitivity reactions to allopurinol. They reportedthat recombinant uricase is under study for the treat-ment of refractory gout and that modification of uricase

with polyethylene glycol (PEG) to reduce its antigenic-ity and prolong its half-life appeared critical for long-term use [9••,10••,11•].

UricaseNative and recombinant uricaseUricase (urate oxidase, EC 1.7.3.3.) catalyzes the oxidationof uric acid into the more soluble allantoin, which isreadily excreted by the kidneys (Fig. 1). Although uricase ispresent in most mammals, humans lack this enzymebecause of a nonsense mutation in exon 2 [12]. Thus,uric acid levels in humans are 10 to 50 times that found inother mammals and may precipitate out of solution andcause gout. For nearly 40 years, investigators have adminis-tered uricase from a variety of animals and micro-organisms to patients to treat hyperuricemia and gout.These treatments with native uricase have been shown todecrease serum uric acid concentrations and thus havebeen found effective in the treatment of hyperuricemia andgout, as well as in prophylaxis and treatment of tumor lysis hyperuricemia. Native uricase purified from Aspergillusflavus had been available in France and Italy for over 20years, but is no longer available. Rather, this same company

Although allopurinol has been available for approximately50 years, hyperuricemia and its sequelae are not only preva-lent, but the incidence and costs associated with this disor-der continue to increase. However, several new therapieshave been developed. Recombinant urate oxidase has beenuseful in the treatment of tumor lysis hyperuricemia, andpegylated urate oxidase shows promise in patients withhyperuricemia and gout. Febuxostat and Y-700 are new oralxanthine oxidase inhibitors that are in human clinical trials.Tailoring of antilipid therapy in selected hyperuricemic andhyperlipidemic patients with fenofibrate may be of benefitin lowering blood cholesterol and uric acid levels. Similarly,treatment of selected hyperuricemic patients who also arehypertensive with losartan or amlodipine may be beneficialin lowering blood pressure and hyperuricemia. Despitethese advances, new treatments for hyperuricemiaare needed.



Serum Uric Acid–Lowering Therapies • Bomalaski and Clark 241

biosynthesized recombinant A. flavus uricase in the yeast Saccharomyces cerevisiae(rasburicase). Rasburicase is atetrameric protein with identical subunits of a molecular mass of approximately 34 kDa. The molecular formula of the monomer is C 1523 H2383 N417O462 S7, and it is a single301 amino acid polypeptide chain with no intra- or inter-disulfide bridges and is N-terminal acetylated. Modifica-

tion of a reactive cysteine may explain some of the differ-ences between rasburicase and native uricase [13]. Becausehumans do not make uricase, all of these uricase enzymesare highly antigenic, and multiple administrations of native uricase have resulted in allergic reactions, anaphy-laxis, and even death. In 2002, rasburicase becameavailable in the US to treat hyperuricemia caused by tumor lysis syndrome, and the initial studies that were the basisfor regulatory approval have been published [14–17].These studies excluded patients with a history of significant atopic allergy or bronchial asthma. They reported that despite excluding patients that account for 8% to 10% of the population studied, antibodies to uricase still occurred

in 7% to 14% of patients treated [18,19].Rasburicase has been approved in the US only for the

initial management of uric acid levels in pediatric patientswith leukemia, lymphoma, and solid tumor malignancieswho are receiving anticancer therapy expected to result intumor lysis and subsequent elevation of plasma uric acid(rasburicase label). In Europe, rasburicase was approvedin 2001 for the treatment and prophylaxis of acutehyperuricemia to prevent acute renal failure in patientswith hematologic malignancy with a high tumor burdenand patients at risk or a rapid tumor lysis or shrinkage at initiation of chemotherapy.

Rasburicase also carries a “black box” warning for ana-phylaxis, hemolysis in patients with glucose-6-phosphatedehydrogenase deficiency, methemoglobinemia, andinterference with uric acid measurements; blood must becollected into prechilled tubes containing heparin antico-agulant, immediately immersed and maintained in an ice-water bath, and assayed within 4 hours of sample collec-tion (rasburicase label). Keeping blood samples frompatients treated with rasburicase at room temperatureresults in false low uric acid levels [20]. Serious adverseevents included fever (5%), neutropenia with fever (4%),respiratory distress (3%), sepsis (3%), neutropenia (2%),

and mucositis (2%). Patients with glucose-6-phosphatedehydrogenase deficiency may have hemolysis caused by hydrogen peroxide formed during the oxidation of uric acid to allantoin (Fig. 1). Rasburicase also is immunogenic in healthy volunteers and can elicit antibodies that inhibit the activity of rasburicase in vitro. In a study of 28 healthy volunteers, the incidence of antibody responses to a singledose or up to five daily doses was assessed. Binding anti-bodies to rasburicase were detected in 17 of 28 (61%)volunteers, and neutralizing antibodies were detected in18 of 28 (64%) volunteers. Time to detection of antibodiesranged from 1 to 6 weeks after rasburicase exposure, andin two subjects antibodies persisted for 333 and 494 days.In patients with hematologic malignancies, 24 of 218patients tested (11%) developed antibodies by day 28 after rasburicase administration.

Thus, patients may receive only one course of rasbu-ricase therapy in their lifetime. Therefore, rasburicasewould not be used on a chronic, repetitive basis in patients

with gout. Rasburicase is given intravenously as a singledaily dose for up to 5 days, and it must be reconstitutedin diluent before administration. The dosage is 0.15 or 0.20 mg/kg per day. Rasburicase treatment together withalkalization at a pediatric oncology center resultedin hypocalcemia in eight of 25 (32%) patients, and hyper-phosphatemia in 10 of 25 (40%) [21]. The authors recom-mended that alkalization be withheld when using rasburicase. This study emphasizes the difficult andsometimes precarious nature of tumor lysis syndrome andits management.

Rasburicase is more effective than intravenous allopu-rinol in tumor lysis hyperuricemia [22], but is more expen-

sive than oral and intravenous allopurinol [23,24].However, rasburicase is cost effective compared with con-ventional treatment in preventing or treating hyperurice-mia and tumor lysis syndrome [25].

More recently, rasburicase has been used effectively intumor lysis hyperuricemia at other centers treating pediatric and adult malignancies, primarily of hematologic origin [26–28,29•,30–33]. There also have been anecdotalreports, during a roundtable discussion, of rasburicase usein gout in the US and Europe [29•]; however, antigenicity of rasburicase would be anticipated to its limit use in gout,because it limits its use in tumor lysis hyperuricemia. Thus,formulation of uricase with polyethylene glycol has beenrecommended [9••,10••,11•].

Uricase Formulated with Polyethylene GlycolCovalent attachment of PEG to a number of therapeutic proteins results in reduction in antigenicity and prolonga-tion in circulating half-life [34•]. This technology hasrecently been applied to uricase from pig and baboon [35],A. flavus [36] and Candida utilis [37•]. Uricase from C. utilishas preferable biochemical features compared with uricasefrom other organisms, including A. flavus (rasburicase).

Figure 1. Urate oxidase (uricase) metabolization of uric acid.Humans do not have uricase, because it has been lost during evolu-tion. In virtually all other mammals, uric acid is metabolized intoallantoin and excreted by the kidney. Uric acid is poorly soluble(approximately 7 mg/100 mL H 2O) compared with allantoin (approx-imately 140 mg/100 mL H 2O). As a consequence, allantoin is muchmore soluble and easily excreted by the kidney.



242 Crystal Arthritis

These preferable features include the highest affinity for uric acid and greatest catalytic rate at physiologic pH. Urateoxidase from C. utilis also can be expressed in Escherichiacoli, and formulated with PEG of 20,000 molecular weight,which is the same size PEG used safely in dimer form on

interferon–alpha-2. This pegylated uricase (uricase-PEG20) has demonstrated safety and efficacy in mice and inhumans with hyperuricemia and gout (Bomalaski, Per-sonal observation) [38,39]. It is administered by the intra-muscular route instead of the intravenous route likerasburicase. Uricase-PEG 20 may be simply withdrawnfrom a vial, like cortisone preparations, and injected; it does not need to be reconstituted with diluent like rasbu-ricase. Clinical trials in humans with uricase-PEG 20 areongoing. To date, this pegylated uricase has demonstrateda dose-dependent decrease in blood uric acid and has beensafe in humans without development of anti-uricase anti-bodies or allergic reactions (Bomalaski, Personal observa-

tion). Doses as low as 0.5 IU/kg (0.062 mg/kg) have beeneffective, with pharmacokinetics of approximately 8 days.Thus, significantly less uricase-PEG 20 needs to be admin-istered (0.062 mg/kg) once, compared with rasburicase(0.15 to 0.2 mg/kg) given daily for up to 5 days. Hemolysismay be a potential side effect in patients with glucose-6-phosphate deficiency, as with rasburicase (Fig. 2). Thus,from these preliminary studies, uricase-PEG 20 wouldappear safer than the nonformulated recombinant uricase(rasburicase). Uricase-PEG 20 may be useful in the chronic treatment of gout because it is less immunogenic than ras-buricase and may be thus more frequently administeredlike pegylated interferons for hepatitis C [34•].

Uricase-PEG 20 may be of benefit in patients withhyperuricemia and gout who do not respond to conven-tional therapeutic interventions (Table 1). This wouldinclude patients with allopurinol intolerance or allergy, or tophi, who have poorly controlled recurrent attacks withcurrent treatment. Patients with renal insufficiency alsomay be candidates for peglylated uricase, because allopu-rinol is excreted through the kidneys. Organ transplant patients with recurrent gouty attacks or tophi also may becandidates, especially to shrink and hopefully eliminatetophi. Patients with acute attacks of gout that do not

respond quickly to or are intolerant of current therapy alsomay be candidates. Acute attacks of gout, even treated withprednisone, take 6 to 8 days for resolution [39]. Patientswith hyperuricemia caused by tumor lysis also may be can-didates for peglylated uricase; patients would be antici-pated to require only one dose compared with the multipleinjections of rasburicase.

Another pegylated uricase called puricase, given intrave-nously, has been reportedly tested in initial human phase Istudies. However, the results from this clinical study, aswell as preclinical studies, have not been reported in themedical literature (PubMed search January 19, 2004).Thus, further comments on this compound cannot bemade at this time.

Xanthine Oxidase InhibitorsAllopurinol is the best known xanthine oxidase (xanthine-oxygen oxidoreductase, EC 1.2.3.2) inhibitor. However, the

side effects of allopurinol, including rash and hepatotoxic-ity, have led investigators to seek other potential xanthineoxidase inhibitors [40]. Natural plant products reportedly used by indigenous people of North America have demon-strated some xanthine oxidase inhibition [41]. Similar invitro inhibitory activity has been observed with some Chi-nese medicinal plants [42]. However, the inhibitory activ-ity in humans has not been demonstrated. Xanthineoxidase inhibition with synthetic 2-styrylchromones alsohas been demonstrated in the laboratory, but not inhumans [43].

More recently, a series of 1-phenylpyrazoles have dem-onstrated xanthine oxidase inhibitory activity in vitro and

in a rat model of hyperuricemia [44]. Of the compoundsprepared, 1-(3-cyano-4-neopentyloxyphenyl) pyrazole-4-carboxylic acid (Y-700) had the most potent enzyme inhi-bition and displayed longer-lasting hypouricemic actionthan allopurinol in a rat model of hyperuricemia. Thepharmacokinetics and pharmacodynamics of Y-700 hasbeen evaluated in Japanese health male volunteers [45]. Y-700 was rapidly absorbed orally, and was eliminated withT 1/2 of 23.5 to 40.2 hours. Urinary excretion was less than1.5% at doses of 0.5 to 80 mg. Thus, Y-700 may be safe inpatients with renal failure. Higher (120 mg) and repetitivedosing (once daily for 10 days) also has been assessed inmale volunteers [46]. No serious adverse events werereported, although abdominal cramps, abdominal pain,and flatulence occurred. Y-700 decreased serum uric acid ina dose- and time-dependent manner. The pharmacokinet-ics was linear, suggesting that once-daily dosing would beappropriate. Only approximately 1% of Y-700 was elimi-nated in the urine.

Febuxostat (TMX-67) is another new xanthine oxidaseinhibitor that binds to the enzyme in a mode different from allopurinol and oxypurinol [47]. Febuxostat is a non-purine inhibitor compared with allopurinol and its metab-olites, which inhibit other enzymes involved in purine and

Figure 2. Uricase formulated with polyethylene glycol (PEG). Uricasecan be formulated with PEG. Pegylation results in a coating arounduricase that decreases its immunogenicity and increases its circulatinghalf-life. Use of the longer 20,000 mw PEG molecule to form uricase-PEG 20 results in little change in the specific activity of uricase(approximately 10 IU/mg to 8.6 IU/mg), compared with PEG of 5000mw (approximately 10 IU/mg to 5 IU/mg) [37•,38]. PEG of 20,000mw was attached to uricase via the primary amines. There are atotal of 33 primary amines on uricase, and PEG was attached toapproximately 66%.




pyrimidine metabolism [48]. This drug is a more potent inhibitor of xanthine oxidase in vitro and in animals thanallopurinol. The pharmacokinetics and pharmacodynam-ics of febuxostat 80 mg orally once per day for 7 days havebeen evaluated in male and female subjects with normaland abnormal renal function [49]. No serious adverse

events were reported, although diarrhea, abdominal pain,and headache occurred. There was no clinically significant change in the pharmacodynamics with increasing renalimpairment. Based on this study, dose adjustment for renaldysfunction does not appear necessary. An 8-week dose-response (10, 20, or 40 mg daily) clinical trial in Japanesesubjects with gout or hyperuricemia has been reported[50]. Febuxostat reduced serum uric acid levels in a dose-dependent manner and was equally effective in under-excretors and over-producers. The most frequent sideeffects were gout flare, common cold syndrome, and ele-vated C-reactive protein, creatine kinase, and serumglutamate pyruvate transaminase; three of 96 (3%) febux-

ostat-treated subjects prematurely terminated the treat-ment because of adverse events.

Febuxostat and Y-700 are promising oral xanthine oxi-dase inhibitors. Further studies in larger patient groups areneeded to confirm their effectiveness and safety. Combina-tion therapy with allopurinol also should be investigated.

Fenofibrate, Losartan, and AmlodipineFenofibrate, a hypolipidemic fibric acid derivative, andlosartan, an angiotensin II receptor antagonist, have beenreported to reduce serum uric acid through enhanced renalclearance. These agents were studied in combination withthe antihyperuricemic agents benzbromarone (50 mg oncedaily) or allopurinol (200 mg twice a day) [51]. Benzbro-marone was used for underexcretory gout and allopurinolfor overexcretors of uric acid. The addition of fenofibrate(300 mg once daily) to hypertriglyceridemic patients withgout taking benzbromarone or allopurinol resulted in astatistically significant drop in serum uric acid at 2 months,although the effects were modest (350.9 mol/L to 297.4mol/L for benzbromarone, and 362.8 mol/L to 309.3 mol/L for allopurinol). Similarly, addition of losartan (50 mg once daily) to hypertensive patients with gout receiving

benzbromarone or allopurinol for 3 months resulted ina statistically significant, but modest, drop in uric acid(285.5 mol/L to 261.7 mol/L for benzbromarone, and356.9 mol/L to 327.1 mol/L for allopurinol). This approxi-mately 15% lowering of uric acid with fenofibrate andbenzbromarone or allopurinol was less than that observedin a prior study with fenofibrate and allopurinol [52],but similar to that observed in a prior study of fenofibrate(200 mg per day) and losartan in non-diabetes patientswith hypertension treated for 8 weeks [53].

Another study used fenofibrate (200 mg per day) inpatients with gout on allopurinol (300 to 900 mg per day)[54]. Fenofibrate was associated with a 19% reduction inserum urate after 3 weeks of treatment. Long-term treat-ment of two patients with fenofibrate resulted in sustainedreduction in lipid levels, with remission from recurrent attacks of gout [55]. There is a similar case reporting theusefulness of fenofibrate [56].

Fenofibrate (200 mg per day) also was investigated in an

8-week trial in patients without diabetes with hypertensiontreated with indapamide, which is associated with hyper-uricemia [57]. Indapamide induced hyperuricemia, becauseof a decrease in the fractional excretion of uric acid, and wasreversed in a statistically significant manner with feno-fibrate, because of an in-urate excretion. Thus, fenofibratemay correct the hyperuricemia induced by indapamide.

This modest effect of fenofibrate and losartan nonethe-less may be useful for patients with hypertension andhyperlipidemia associated with gout; their role in asympto-matic hyperuricemia remains to be elucidated [58]. Losar-tan is not without side effects; a case of exercise-inducedacute renal failure with hypouricemia, and acute tubular

necrosis with interstitial necrosis has been reported [59].The role of long-term fenofibrate therapy on hyperurice-mia and attacks of gout in patients with hyperlipidemiais not yet determined. The fenofibrate decrease in serumuric acid is modest (approximately 15% to 20%) and hasonly been evaluated in short-term studies. Longer-termstudies are needed to attempt to confirm its usefulness aschronic therapy in patients with hyperuricemia.

Amlodipine, a calcium channel blocker, also has beeninvestigated in cyclosporin-induced hyperuricemia inhypertensive renal transplant recipients [60]. Patients ona stable dose of cyclosporin were randomized to receiveamlodipine (5 to 10 mg per day) or the beta-adrenorecep-tor antagonist tertatolol (5 to 10 mg per day) for 60 days.Amlodipine statistically significantly decreased serumuric acid, although the effect was modest (483 mol/L to431 mol/L). Tertatolol significantly increased serum uric acid. Amlodipine may be useful in treatment of hyper-tension in hypertensive, hyperuricemic renal transplant patients. Benziodarone and allopurinol have been shownto be effective in controlling hyperuricemia in renal trans-plant patients, and benziodarone at greater than 75 mg per day is statistically significantly more effective thanallopurinol [61].

Table 1. Gout patients that may be candidates foruricase-polyethylene glycol 20

Organ transplant patients with recurrent gout attacksor tophi

Allopurinol allergy patientsRenal insufficiency patientsTumor lysis hyperuricemia patientsAcute gout attacks not responding to conventional

treatmentsChronic gout patients not responding to conventional

treatments




Other TherapiesConsumption of two servings (280 g) of bing cherries hasbeen shown to significantly lower plasma urate in women[62]. The availability, feasibility, and duration of thisdietary intervention are not yet determined. Near-irondeficiency–induced anemia also has been evaluated [63].Quantitative phlebotomy over 28 months markedly diminished gout attacks. Such treatment cannot be recom-mended at the present time, given the potential side effectsof anemia and the availability of current antihyperuricemiaand antigout agents.

Although not directly antihyperuricemic, recent reportsremind us of the use of drugs used in the treatment of thepatient with gout. A variety of corticosteroid preparationsare available for intra-articular injection. In the rat sub-cutaneous air pouch model of inflammation induced by monosodium urate crystals, betamethasone injectionresulted in significantly fewer crystals compared withtriamcinolone hexacetonide and prednisolone tebutate,

which also produced atrophy and necrosis of themembrane [64]. However, each of the preparations by themselves produced very mild transient inflammation,al though overal l inf lammation was diminished.Corticosteroid agents have been shown to be of benefit incontrolling gout inflammation when injected by the intra-articular or intramuscular route, or taken orally [65•].

Allopurinol is antihyperuricemic. However, recent reports remind us that this drug is not without side effects.Allopurinol hypersensitivity syndrome with rash and possi-ble skin sloughing is a feared complication [66]. Somepatients with allopurinol hypersensitivity can be desensi-tized [67]. Allopurinol and benzbromarone are equally

effective in chronic tophaceous gout when optimalserum urate levels are achieved and tophi have shrunk, andcombined therapy may be useful to shrink tophi in patientsthat do not adequately respond to only one agent [68]. Inanother study, benzbromarone was superior to allopurinolin lowering serum urate levels in hyperuricemia patientswithout gout [69]. However, allopurinol may be moreeffective than benzbromarone in its antioxidant ability to scavenge the hydroxyl radical, because of its inhibitory action toward low density lipoprotein oxidation [70].Further studies are needed to confirm these findings. Lastly,hepatic failure also has been reported with benzbromarone[71], as with allopurinol. Thus, significant side effectsmay occur with allopurinol and benzbromarone, as well asbenziodarone, which is another benzofuran [72].

Although not directly focused on hyperuricemia, surgery has been again reported to be of benefit for those patientswith tophaceous gout, especially in those patients with ulcer-ated and infected tophi [73]. In this study of 45 patients, only one third were on allopurinol and only 47% did not have acomplication from surgery. This study reminds us of theimportance of diagnosis and treatment of the underlying hyperuricemia that lead to tophi. The soft-tissue shaving procedure may be useful in improving surgical outcome [74].

Other ThoughtsAlthough initial gout attacks occur more commonly inpatients with hyperuricemia, patients with normouricemiamay present with an acute gout attack. A recent report reminds us that gout attacks in the joint are not invariably accompanied by a uric acid level in the blood that fallsout of the laboratory’s normal range [75]. In this study,27 of 226 (12%) patients were normouricemic at time of diagnosis of gout. Eighty-one percent of those observeddeveloped hyperuricemia at a median of 1 month after diagnosis (range of 1 week to 24 months). Thus, althoughgout attacks with normouricemia do occur, hyperuricemiatypically will be documented in follow-up.

Hyperuricemia leads to gout and also to kidney stones.A more recent study confirms that a history of gout increases the risk of kidney stones by approximately two-fold [76]. Conversely, a history of kidney stones was not associated with increased risk of gout. However, morespecifically, the presence of pure and mixed uric acid

kidney stones was strongly associated with gout, and viceversa [77]. Thus, the identity of the stone provides a clue tothe possible risk of a gouty diathesis.

Treatment of hyperuricemia and gout in patients withheart failure is difficult [78]. Nonsteroidal anti-inflamma-tory drugs may cause fluid retention and colchicine toxicity may occur because of renal and hepatic insufficiency.Allopurinol toxicity is increased in patients taking thiazidediuretics, and allopurinol interacts with anticoagulantsand theophylline. Uricosurics may be useful in diuretic-induced hyperuricemia, but they are not effective in renalinsufficiency. Thus, new treatments for patients with heart failure are needed.

Self-medication for gout was examined and foundto be poorly effective in control of acute attacks andhyperuricemia [79]. Patients with more regular follow-upand those treated with urate-lowering drugs had fewer attacks and lower urate levels. This article re-emphasizesthe intuitive patients with hyperuricemia and gout that receive regular medical care that includes the use andmonitoring of antihyperuricemic agents do better that those left to their own devices.

ConclusionsSignificant numbers of patients have hyperuricemia that ispoorly responsive to current therapies; new therapies willhopefully be more beneficial (Table 2). From a rheumato-logic perspective, translation of the knowledge of treat-ment of tumor lysis hyperuricemia with urate oxidase may result in better control of gout hyperuricemia. Newxanthine oxidase inhibitors will hopefully be safer andmore effective than allopurinol. The addition of feno-fibrate as a lipid and uric acid–lowering agent to selectedhyperuricemic and hyperlipidemic patients may be of benefit. Similarly, the use of losartan or amlodipine tocontrol hypertension in selected hyperuricemic patients




also may be beneficial. New treatments for hyperuricemiaand its rheumatologic, vascular, and nephrologic sequelaeare needed.

AcknowledgmentsGrant support provided by US Food and Drug Administra-tion grant FD-R-002193-01 to Dr. Bomalaski.

Disclosure: Dr. Bomalaski holds stock in Phoenix Pharma-cologics and is a member of their Board of Directors.

References and Recommended Reading Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Arrondee E, Michet CJ, Crowson CS, et al. : Epidemiology of gout: is the incidence rising? J Rheumatol 2002,29: 2403–2406.

2. Zeng Q, Wang Q, Ren C, et al. : Primary gout in Shantou:a clinical and epidemiological study. Chin Med J 2003,116: 66–69.

3. Chen SY, Chen CL, Shen ML, Kamatani N: Trends in themanifestations of gout in Taiwan. Rheumatology 2003,42: 1529–1533.

Table 2. Advantages and disadvantages of current and pipeline antihyperuricemic drugs

Drug Advantages Disadvantages

Allopurinol Prototypical antihyperuricemic agent;reduces urate in under-excretorsand over-producers; single dailydose; can be used in renal sufficiency

Precipitation of acute gout; rash, fatal hypersensitivitysyndromes, and liver and renal toxicity; modify dosewith renal impairment and those taking azathioprine,mercaptopurine, and warfarin

Probenecid Reduces urate levelsin under-excretors

Precipitation of acute gout; rash, GI symptoms, liver andrenal toxicity, and anemia; potential of drug interactionsbecause of interference with renal excretion of other drugs;contraindicated with renal dysfunction (creatinine clearance<50 mL/minute) and renal stones; use with caution in patientswith heparin anticoagulation

Sulfinpyrazone Reduces urate levelsin under-excretors

Precipitation of acute gout; rash, GI symptoms, bone marrowsuppression (congener of phenylbutazone), antiplatelet activity;contraindicated with renal dysfunction (creatinine clearance<50 mL/minute) and renal stones; not universally available

Benzofurans(benzbromaroneand benziodarone)

Reduces urate levels in under-excretors; uricosuric in renaltransplant recipients; no interactionwith azathioprine; effective evenwith renal dysfunction (creatinineclearance <50 mL/minute)

Precipitation of acute gout; GI symptoms, jaundice, thyroiddisorders; acute uric acid nephropathy; not universally available

Rasburicase Rapid lowering of urate level; usefulin tumor lysis syndrome

Intravenous administration; rash and allergic reactions; onlyone course of treatment per lifetime; methemoglobinemia;interference with uric acid measurements; hemolysis inpatients with glucose-6-phosphate deficiency because of H2O 2 production

Uricase-PEG 20 Rapid lowering of urate level;potentially useful in organ transplantpatients with gout, tumor lysissyndrome, tophaceous gout,renal failure, and acute gout attacks;intramuscular administration

Potential allergic reactions (foreign protein); potential hemolysisin patients with glucose-6-phosphate deficiency because of H2O 2 production; long-term use not known

Y-700 May be safe in patientswith renal failure

GI symptoms; long-term use not known

Febuxostat (TMX-67) May be safe in patients with renalfailure; lowers urate in under-excretors and over-producers

Gout flare, common cold syndrome, elevated C-reactive protein,creatinine kinase and SGPT; long-term use not known

GI gastrointestinal; SGPT serum glutamate pyruvate transaminase; uricase-PEG 20 uricase formulated with polyethylene glycol of 20,000molecular weight.




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7.•• Johnson RJ, Kang DH, Feig D, et al. : Is there a pathogenetic role for uric acid in hypertension and renal disease?Hypertension 2003, 41: 1183–1190.

Review article describing the association of hyperuricemia with hyper-tension, vascular disease, renal disease, and cardiovascular events.

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9.•• Terkeltaub RA: Clinical practice: gout. N Engl J Med 2003,349: 1647–1655.

Excellent review article on gout using a patient presentation as aspringboard for discussion. Includes easy-to-read figures and tablesthat summarize treatment regimens and considerations in therapy.10.•• Rott KT, Agudelo CA: Gout. JAMA2003, 289: 2857–2860.Excellent review article on gout emphasizing comorbidities and

characteristics of classic versus atypical gout.11.• Pay S, Terkeltaub RA: The case for uricase in gout. Curr Rheumatol

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activity in hominoids and its evolutionary implications.Mol Biol Evol2002, 19: 640–653.

13. Bayol A, Capdevvielle J, Malazzi P, et al. : Modification of areactive cysteine explains differences between rasburicaseand uricozyme, a natural Aspergillus flavus uricase. BiotechnolAppl Biochem2002, 36:21–31.

14. Pui C-H, Mahmoud HM, Wiley JM, et al. : Recombinant urateoxidase for the prophylaxis or treatment of hyperuricemiain patients with leukemia or lymphoma. J Clin Oncol 2001,19: 697–704.

15. Pui C-H, Jeha S, Irwin D, Camitta B: Recombinant urateoxidase (rasburicase) in the prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a compassionate-use trial. Leukemia 2001,15: 1505–1509.

16. Pui C-H: Urate oxidase in the prophylaxis or treatment of hyperuricemia: the United States experience. Semin Hematol2001, 38(suppl): 13–21.

17. Goldman ST, Holcenberg JS, Finklestein JZ, et al. : A random-ized comparison between rasburicase and allopurinol inchildren with lymphoma or leukemia at high risk for tumor lysis. Blood2001, 97: 2998–3003.

18. Pui C-H: Rasburicase: a viewpoint. Paediatr Drugs 2001, 3:438.19. Goldman S: Rasburicase: a viewpoint. Paediatr Drugs 2001,

3:439.20. Lim E, Bennett P, Beilby J: Sample preparation in patients

receiving uric acid oxidase (rasburicase) therapy. Clin Chem2003, 49: 1417–1419.

21. van den Berg H, Reintsema AM: Renal tubular damage inrasburicase: risks of alkalinisation. Ann Oncol 2004,5:175–176.

22. Pui C-H: Rasburicase: a potent uricolytic agent. Expert OpinPharmacother 2002, 3:433–442.

23. Holdsworth MT, Nguyen P: Role of iv allopurinol and rasbu-ricase in tumor lysis syndrome. Am J Health Syst Pharm 2003,60: 2213–2222.

24. Yim BT, Sims-McCallum RP, Chong PH: Rasburicase for thetreatment and prevention of hyperuricemia. Ann Pharmacother 2003, 37: 1047–1054.

25. Annemans L, Moeremans K, Lamotte M, et al. : Pan-Europeanmulticenter economic evaluation of recombinant urateoxidase (rasburicase) in prevention and treatment of hyper-uricemia and tumor lysis syndrome in hematological cancer patients. Support Care Cancer 2003, 11: 249–257.

26. Cairo MS: Prevention and treatment of hyperuricemia inhematological malignancies. Clin Lymphoma 2002,3(suppl): S26–S31.

27. Hummel M, Buchheidt D, Reiter S, et al. : Successful treatment of hyperuricemia with low doses of recombinant urateoxidase in four patients with hematologic malignancy andtumor lysis syndrome. Leukemia 2003, 17: 2452–2544.

28. Lee AC, Li CH, So KT, Chan R: Treatment of impending tumor lysis with single-dose rasburicase. Ann Pharmacother 2003,37: 1614-1617.

29.• Navolanic PM, Pui C-H, Larson RA, et al.: Elitek-rasburicase: aneffective means to prevent and treat hyperuricemia associatedwith tumor lysis syndrome, a Meeting Report, Dallas, Texas,January 2002. Leukemia 2003, 17:499–514.

A meeting report on the role of rasburicase in tumor lysis hyperuricemia.30. Goldman S: Rasburicase: potential role in managing tumor

lysis in patients with hematological malignancies. Expert RevAnticancer Ther 2003, 3:89–93.

31. Ribeiro RC, Pui C-H: Recombinant urate oxidase for preven-tion of hyperuricemia and tumor lysis syndrome in

lymphoid malignancies. Clin Lymphoma 2003, 3:225–232.32. Bosly A, Sonet A, Pinkerton CR, et al. : Rasburicase (recombi-

nant urate oxidase) for the management of hyperuricemia inpatients with cancer: report of an international compassion-ate use study. Cancer 2003, 98: 1048–1054.

33. Coiffier B, Mounier N, Bologna S, et al. : Efficacy and safety of rasburicase (recombinant urate oxidase) for the preventionand treatment of hyperuricemia during induction chemo-therapy of aggressive non-Hodgkin’s lymphoma: results of the GRAAL1 (Groupe d’Etude des Lymphomes de l’AdulteTrial) on rasburicase activity in adult lymphoma study. J ClinOncol 2003, 21: 4402–4406.

34.• Harris JM, Chess RB: Effect of pegylation on pharmaceuticals.Nature Rev Drug Disc 2003, 2:214–221.

Excellent short review on the principles of pegylation and applicationto biologics.35. Kelly SJ, Delnomdedieu M, Oliverio MI, et al.: Diabetes insipidus

in uricase-deficient mice: a model for evaluating therapy withpoly(ethylene glycol)-modified uricase. J Am Soc Nephrol2001,12:1001–1009.

36. Vivarès D, Bonneté F: X-ray scattering studies of Aspergillusflavus urate oxidase: towards a better understanding of PEGeffects on the crystallization of large proteins. Acta Cryst 2002, D58: 472–479.

37.• Bomalaski JS, Holtsberg FW, Ensor CM, Clark MA: Uricaseformulated with polyethylene glycol (uricase-PEG 20):biochemical rationale and preclinical studies. J Rheumatol2002, 29: 1942–1949.

Description of the rationale for choosing C. utilis uricase and poly-ethylene glycol of 20,000 mw to optimize formulation of the enzyme,and results from preclinical testing.38. Bomalaski JS, Goddard DH, Grezlak D, et al. : Phase I study

of uricase formulated with polyethylene glycol (uricase-

PEG 20). Arthritis Rheum 2002, 46(suppl): S141.39. Silveria LH, Vargas A, Medina MN: Use of low-dose prednisonein the treatment of the acute gouty attack (AGA). ArthritisRheum 2003, 48(suppl): S535.

40. Borges F, Fernandes E, Roleira F: Progress towards the discovery of xanthine oxidase inhibitors. Curr Med Chem 2002,9:195–217.

41. Owen PL, Johns T: Xanthine oxidase inhibitory activity of northeastern North American plant remedies used for gout.J Ethnopharmacol 1999, 64: 149–160.

42. Kong LD, Cai Y, Huang WW, et al. : Inhibition of xanthineoxidase by some Chinese medicinal plants used to treat gout.J Ethnopharmacol 2000, 73: 199–207.




43. Fernandes E, Carvalho F, Silva AM, et al. : 2-styrylchromonesas novel inhibitors of xanthine oxidase: a structure-activity study. J Enzyme Inhib Med Chem 2002, 17: 45–48.

44. Isibuchi S, Morimoto H, Oe T, et al. : Synthesis and structure-activity relationships of 1-phenylpyrazoles as xanthineoxidase inhibitors. Bioorg Med Chem Lett 2001, 11: 879–882.

45. Osajima T, Kamezawa M, Fukunari A, et al. : Pharmacokineticsand pharmacodynamics of Y-700, a potent and non-renalexcretion type of xanthine oxidase inhibitor, in healthy malevolunteers. Arthritis Rheum 2003, 48(suppl): S530.

46. Noma S, Verho M, Iwane, et al. : Safety, tolerability, pharmaco-kinetics, and lowering uric acid effect of repeated daily dosing with Y-700, a novel xanthine oxidase inhibitor, inhealth male volunteers. Arthritis Rheum 2003, 48(suppl): S530.

47. Okamoto K, Eger BT, Nishino T, et al. : An extremely potent inhibitor of xanthine oxidoreductase: crystal structure of theenzyme-inhibitor complex and mechanism of action. J BiolChem 2003, 278: 1848–1855.

48. Zhao L, Takano Y, Horiuchi H: Effect of febuxostat, a novelnon-purine, selective inhibitor of xanthine oxidase (NP-SIXO) on enzymes in purine and pyrimidine metabolismpathway. Arthritis Rheum 2003, 48(suppl): S531.

49. Swan S, Khosravan R, Mayer MD, et al. : Effect of renal impair-ment on pharmacokinetics, pharmacodynamics, and safety of febuxostat (TMX-67), a novel non-purine selective inhibitor of

xanthine oxidase. Arthritis Rheum 2003, 48(suppl): S529.50. Kamatani N, Fujimori S, Hada T, et al. : Phase II dose-response

clinical trial using febuxostat (TMX-67), a novel-type xanthineoxidase/xanthine dehydrogenase inhibitor, for gout andhyperuricemia. Arthritis Rheum 2003, 48(suppl): S530.

51. Takahashi S, Moriwaki Y, Yamamoto T, et al. : Effects of combi-nation treatment using anti-hyperuricaemic agents withfenofibrate and/or losartan on uric acid metabolism. AnnRheum Dis 2003, 62:572–575.

52. Hepburn AL, Kaye SA, Feher MD: Fenofibrate: a new treatment for hyperuricemia and gout? Ann Rheum Dis 2001, 60:984-986.

53. Elisaf M, Tsimichodimos V, Bairaktari E, et al. : Effect of micron-ized fenofibrate and losartan combination on uric acidmetabolism in hypertensive patients with hyperuricemia.J Cardiovasc Pharmacol 1999, 34: 60–63.

54. Feher MD, Hepburn AL, Hogarth MB, et al.: Fenofibrate enhancesurate reduction in men treated with allopurinol for hyper-uricaemia and gout. Rheumatology 2003, 42:321–325.

55. Hepburn AL, Kaye SA, Feher MD: Long-term remission fromgout associated with fenofibrate therapy. Clin Rheumatol2003, 22: 73–76.

56. Millionis HJ, Elisaf MS: Management of hypertension anddyslipidaemia in patients presenting with hyperuricemia:case histories. Curr Med Res Opin 2000, 16: 164–170.

57. Achimastos A, Liberopoulos E, Nikas S, et al. : The effects of theaddition of micronised fenofibrate on uric acid metabolismin patients receiving indapamide. Curr Med Res Opin 2002,18: 59–63.

58. Bardin T: Fenofibrate and losartan. Ann Rheum Dis 2003,62: 497–498.

59. Ito O, Hasegawa Y, Sato K, et al. : A case of exercise-inducedacute renal failure in a patient with idiopathic renal hypo-uricemia developed during antihypertensive therapy withlosartan and trichlormethiazide. Hypertension Res 2003,26: 509–513.

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62. Jacob RA, Spinozzi GM, Simon VA, et al. : Consumption of cherries lowers plasma urate in healthy women. J Nutr 2003,133: 1826–1829.

63. Facchini FS: Near-iron deficiency-induced remission in gouty arthritis. Rheumatology 2003, 42: 1550–1555.

64. Rull M, Clayburne G, Sieck M, Schumacher HR: Intra-articular corticosteroid preparations: different characteristics andtheir effect during inflammation induced by monosodiumurate crystals in the rat subcutaneous air pouch. Rheumatology 2003, 42: 1093–1100.

65.• Kim KY, Schumacher HR, Hunsche E, et al. : A literature review of the epidemiology and treatment of acute gout. Clin Ther 2003, 25: 1593–1617.

Excellent review of the epidemiology, treatment, and burden of illnessfor acute gout.66. Anderson BE, Adams DR: Allopurinol hypersensitivity syndrome.

J Drugs Dermatol 2002, 1:60–62.67. Hoffman LA: My gout and allopurinol desensitization. J Clin

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70. Tsutsumi Z, Moriwaki Y, Takahashi S, et al. : Oxidized low-density lipoprotein autoantibodies in patients with primary gout: effect of urate-lowering therapy. Clin Chim Acta 2004,339: 117–122.

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72. Franco A, Jimenez L, Torralba J, et al. : Acute uric acid nephrop-athy by overdosage of benziodarone in a renal transplant recipient. Nephron 2002, 92: 746–747.

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76. Kramer HJ, Choi HK, Atkinson K, et al. : The association betweengout and nephrolithiasis in men: the Health Professionals’Follow-Up Study. Kidney Int 2003, 64:1022–1026.

77. Pak CY, Poindexter JR, Adams-Huet B, Pearle MS: Predictivevalue of kidney stone composition in the detection of meta-bolic abnormalities. Am J Med 2003, 115: 26–32.

78. Spieker LE, Ruschitzka FT, Lüscher TF, et al. : The management of hyperuricemia and gout in patients with heart failure.Eur J Heart Fail 2002, 4:203–410.

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