gout is a form of inflammatory arthritis characterized by the formation of monosodium urate crystals in the joints , synovial liquid , and other tissues [ 14 ] .
it is one of the most prevalent causes of arthritis [ 47 ] and recent studies suggest that the prevalence and incidence of gout has increased in the last decades [ 2 , 8 , 9 ] . in the usa ,
the cumulative incidence of gout is 8.6% in men and its prevalence in the general population is approximately 0.5% [ 1 , 2 ] .
the disease affects approximately 1 - 2% of adult males in occidental countries [ 1 , 4 , 7 ] , with a male  :  female ratio of 35  :  1 . according to the framingham study ,
9.2% of men and 0.4% of women had hyperuricemia and 19% of them developed gout .
persistent elevation of serum urate levels is the essential condition leading to the development of gout .
about 10% of people with hyperuricemia develop gout and 90% of patients with gout are hyperuricaemic .
risk factors include family history , excessive consumption of alcohol , use of diuretics , kidney disease [ 1 , 2 , 6 , 9 ] , dietary factors such as elevated consumption of seafood , meat , and vegetables rich in purines [ 1 , 2 , 4 , 6 , 9 ] , elevated body mass index ( bmi ) [ 1 , 4 , 6 , 9 ] , age , and gender .
initial clinical presentation is commonly an acute inflammatory monoarthritis affecting the first metatarsophalangeal joint , known as podagra [ 1 , 2 , 4 ] .
the presence of urate crystals in the synovial fluid is considered the gold standard in diagnosing gout .
the treatment of an acute gout crisis focuses on controlling pain and inflammation [ 4 , 6 ] .
drugs such as colchicine , anti - inflammatories , and analgesics are part of the therapeutic regime for gout .
once the acute crisis is controlled , drugs that reduce uric acid such as allopurinol are widely prescribed [ 4 , 6 ] .
benzbromarone is an uricosuric agent that has been used for more than 25 years to control hyperuricemia .
it inhibits the main renal urate transporter , urat-1 , an exchanger located in the luminal face of the proximal tubule of the kidney . in doing so
benzbromarone is metabolised in the liver by the cytochrome p450 system , and as a result should be used with caution in patients with hepatobiliary diseases . however , benzbromarone is no longer commercially available in usa , and in 2003 it was withdrawn from the european market due to the risk of severe hepatotoxicity .
there are case reports of fulminant hepatitis associated with the usage of standard doses of benzbromarone ( 100  mg / day ) during short periods ( three months ) .
nevertheless , only three cases have been described since the early 1970s and it is debated whether banning benzbromarone was appropriate or if it was done too hastily . in brazil ,
sales are permitted by the brazilian health surveillance agency ( anvisa ) and benzbromarone seems to have a safety profile identical to sulfinpyrazone . besides hepatotoxicity
, at times of the intense uric acid excretion benzbromarone causes may lead to the formation of uric acid kidney stones .
patients should be advised to stop benzbromarone and seek urgent medical attention if they develop nausea , vomiting , abdominal pain , or jaundice .
benzbromarone also increases the metabolism of warfarin increasing the risk of bleeding in patients using both medications at the same time .
there are few studies in the medical literature evaluating the metabolism of benzbromarone , its side effects , and also its risks and benefits .
the objective of this study is to describe the profile of a sample of gouty patients treated with allopurinol , benzbromarone , or a combination of these two drugs , as well as to describe the impact of this therapy on lowering uric acid levels .
we evaluated 48 patients diagnosed with gout who were seen at the outpatient rheumatology clinic at the federal university of paran between january 2009 and november 2010 .
the study was approved by the teaching hospital 's ethics committee and informed consent was obtained from all patients . an observational
the following data were collected : age ; gender ; profession ; personal history of alcohol , tobacco , or drug use ; comorbidities such as obesity , high blood pressure ( hbp ) , diabetes mellitus ( dm ) , hypertriglyceridemia , nephrolithiasis , and osteoarthritis ; family history of gout ; year of onset ( first attack ) , total number of attacks , average duration of attacks ( days ) , triggering factors , joint affected in the first attack , and other joints involved as the disease evolved ; presence or absence of tophi ; daily dosage ; and how long each medication had been used .
serum creatinine , basal and posttreatment serum levels of uric acid , transaminase , and bilirubin were measured .
the patients were divided into three groups : patients using only allopurinol ( a ) , only benzbromarone ( b ) , and both in combination ( a + b ) .
treatment for each patient was selected on a case - by - case basis by attending physicians and the head of the clinic .
allopurinol was started in doses from 100 to 300  mg / day , with progressive increases according to therapeutic response .
benzbromarone was started at a dose of 50  mg / day during the first month and was increased later , if necessary , to 100  mg / day .
uric acid levels were checked every three months . the treatment period with uricosurics ranged from 12 to 18 months .
the results were analysed by variance analysis , t - test , paired t - test , and nonparametric tests ( wilcoxon and mann - whitney ) , when necessary .
the average age of these patients was 56.6  11.4 years , with variation from 35 to 81 years .
more than 70% of the individuals had acute monoarthritis in the first metatarsophalangeal joint at some point in the evolution of the disease and approximately 40% of them experienced their first gout attack in this joint .
almost half of the patients had chronic tophaceous gout ( table 1 ) . approximately half of the patients identified factors that triggered acute attacks , and the majority of acute attacks were triggered by dietary factors ( 31.2% ) and alcohol consumption ( 29.1% ) .
other triggers in our sample included local trauma , cold , physical exercise , and the use of diuretics .
about 80% of the patients had high blood pressure , 20% had diabetes mellitus , 40% had hypertriglyceridemia , and 20% were obese .
serum creatinine levels were 1.4  0.8  mg / dl ( a variation of 0.65.4  mg / dl ) and uric acid levels in the urine were 555  356  mg / day ( variation of 1382132  mg / day ) .
58.3% of the patients were considered to be uric acid hypoexcretors ( excretion below 400  mg / day ) .
no patient experienced alteration of bilirubin or transaminases . with regard to the medications used , 31 ( 64.5% ) patients used colchicine , with daily doses between 0.5 and 1  mg .
approximately 40% of the patients were using nonsteroidal anti - inflammatories ( nsaids ) and 18.75% used corticosteroids .
the entire patient group experienced a significant drop in uric acid levels , from 8.5  1.8 to 6.7  2.1  mg / dl ( p < 0.001 ) , regardless of the prescribed medication class ( figure 1 ) .
thirty - eight patients used hypouricemics : allopurinol was prescribed to 27 patients and benzbromarone to four patients , and these two drugs were combined in seven cases .
there were no significant differences in age , uric acid levels in urine , or serum urate levels at the beginning of the treatment ( table 2 ) .
when comparing the base serum urate levels with the final serum urate levels obtained in this study , there was a significant difference between patients taking only allopurinol and patients taking benzbromarone alone or both drugs together ( table 2 and figure 2 ) . the number of patients taking both drugs whose serum urate values were within normal range ( men < 7  mg / dl and women < 6  mg / dl ) was 85.7% ( 6/7 ) , while for the group taking benzbromarone alone this value was 75% ( 3/4 ) , and in the group taking allopurinol alone it was 51.8% ( 14/27 ) .
at a time when new synthetic and biological medications to treat gout are being considered , we revisited a molecule that is already known and used in the therapeutic control of this ancient disease .
eighty percent ( 38/48 ) received hypouricemics . in most cases , allopurinol was the drug of choice to reduce hyperuricemia ( 27/38 , 71% ) .
we observed that , in patients taking allopurinol alone , serum urate levels were higher than in those taking benzbromarone alone or taking a combination of both drugs ( table 2 ) .
there is evidence that standard doses of benzbromarone ( 100  mg / day ) produce stronger hypouricemic effects than standard doses of allopurinol ( 300  mg / day ) [ 11 , 15 , 16 ] . in two
series , benzbromarone reduced uric acid concentration by 54% to 63% and uric acid levels were inferior to 5  mg / dl [ 15 , 17 ] . in a study conducted by perez - ruiz et al . , 53% of patients who received allopurinol and 100% of patients who received benzbromarone achieved plasma urate levels considered optimal for disease control . in another study in which only patients intolerant to allopurinol were analysed ,
92% of patients who received benzbromarone were successfully treated , maintaining serum urate levels at around 5  mg / dl [ 4 , 11 , 17 ] . in our study , allopurinol brought serum urate levels to within normal range in 51.8% of the patients , benzbromarone alone reduced urates to normal levels in 75% of patients , and combination therapy normalized uricaemia in 85.7% of patients .
compared efficacy and tolerability between allopurinol 300600  mg / day and benzbromarone 100200  mg / day .
when doses considered to be lower than the standard were used , uric acid levels were brought to normal levels in 26% of cases using allopurinol and 52% of cases using benzbromarone . with higher doses ,
benzbromarone can be considered for patients with low urate excretion , except if there is a previous history of nephrolithiasis .
patients intolerant to allopurinol or who experience unsatisfactory reduction of urate levels or even primary hyperuricemia with deficiency in kidney urate excretion ( < 400  mg/24  h ) but normal kidney function can be treated with benzbromarone . in our study , the majority of patients using benzbromarone were hypoexcretors of uric acid .
benzbromarone has limited effectiveness in patients with kidney insufficiency   but can be effective in patients with moderate kidney insufficiency . although this drug is less effective in patients with lower creatinine clearance , an important reduction in uric acid levels was observed in these patients .
the serum creatinine levels of patients using benzbromarone varied greatly , with values between 0.8 and 2.3  mg / dl .
we did not measure the patients ' 24-hour creatinine clearance . in the patient group taking both allopurinol and benzbromarone simultaneously , initial serum urate levels of 8.2  1.4  mg / dl decreased about 47.25% to 4.6  2.3 ( p <
this result can be considered superior when compared with the patient group taking allopurinol alone ( figure 2 ) and similar to the result obtained from the group taking benzbromarone alone . in a study performed by yamamoto and collaborators ,
the authors concluded that the interaction did not affect the plasmatic concentration of oxipurinol ( the main allopurinol metabolite ) but caused an increase in oxipurinol clearance .
oxipurinol levels were not measured in our patients . according to perez - ruiz et al .
, benzbromarone , used alone or combined with allopurinol , is superior to therapy with allopurinol in reducing gouty tophi .
this study has limitations : first of all , the choice of therapy was not randomized but was chosen by the attending physician according to each patient 's profile .
similarly , patient followup was not blind ; that is , doctors and patients were aware of which medication was being used in each case .
moreover , although 11 patients received benzbromarone , the number of patients taking this drug alone ( n = 4 ) was very small .
however , we believe that benzbromarone , alone or in combination with allopurinol , has an important clinical role in controlling uricaemia of patients with gout .
patients should be selected carefully to take benzbromarone , and those with liver disease or advanced chronic kidney disease should be excluded . of course , a prospective , randomized double - blind clinical trial involving multiple centres is still needed . as stated by lee and collaborators in a recent revision ,  availability of benzbromarone to treat selected cases of gout
would be especially interesting , particularly to patients in whom allopurinol produces insufficient response or toxicity . 
the therapeutic combination of benzbromarone and allopurinol significantly decreased serum urate levels in patients with gout when compared to the individual use of each of these agents .
this finding is especially important in treating patients who can not control hyperuricemia with monotherapy .
the lack of serious adverse effects associated with benzbromarone in our study is probably related to the selection of suitable patients .
we believe that benzbromarone plays an important role in controlling hyperuricemia and clinical remission of patients with refractory gout .
 
 objective . to profile a sample of gouty patients treated with allopurinol , benzbromarone , or a combination of these two drugs and to describe the impact of this therapy in reducing uric acid levels 
 . methods . 
 an observational , transversal study was performed . 
 we evaluated 48 patients diagnosed with gout who were seen at the outpatient rheumatology clinic of the federal university of paran between january 2009 and november 2010 . 
 clinical data , creatinine serum levels , and basal and posttreatment levels of serum urates , transaminases , and bilirubins were recorded . 
 uric acid levels were measured in a 24-hour urine sample . 
 patients were divided into three groups : patients given only allopurinol ( a ) , only benzbromarone ( b ) , and both in combined therapy ( a + b ) . results . 
 the average age of these patients was 56.6  11.4 years , varying from 35 to 81 years . 
 the entire patient group experienced a significant drop in serum urate levels , from 8.5  1.8  mg / dl ( 0.472  0.1  mmol / l ) to 6.7  2.1  mg / dl ( 0.372  0.116  
 mmol / l ) ( p < 0.001 ) , regardless of the prescribed medication . the number of patients taking both drugs whose serum uric acid values fell within normal range ( men < 7  mg / dl ( 0.38  mmol / l ) and women < 6  mg / dl ( 0.33  mmol / l ) ) was 85.7% ( 6/7 ) while this value for the group taking benzbromarone alone was 75% ( 3/4 ) and for the group taking allopurinol alone this number was 51.8% ( 14/27 ) . conclusions . 
 the therapeutic combination of benzbromarone and allopurinol significantly decreased serum urate levels in patients with gout when compared to individual use of each of these agents . 
 this finding is especially important in treating patients who can not control hyperuricemia with monotherapy . 
 benzbromarone alone or in combination with allopurinol has an important clinical role in controlling hyperuricemia in patients with gout . 
1. Introduction
2. Patients and Methods
3. Results
4. Discussion
5. Conclusion