Richard O. Day

Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis

BACKGROUND Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. METHODS We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). RESULTS Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. CONCLUSIONS In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.

Do Nonsteroidal Anti-inflammatory Drugs Affect Blood Pressure? A Meta-Analysis

Hypertension is prevalent [1, 2] and is a major determinant for stroke and coronary heart disease [3-5]. Further, the higher the blood pressure, the more marked is the reduction in life expectancy [6]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs worldwide when grouped by generic categories [7], accounting for 4% to 9% of all prescriptions in developed countries [8-12]. Since 1967, their use has increased steadily, particularly among elderly persons [13]. Certain NSAIDs have been reported in randomized, controlled trials to elevate blood pressure in some previously normotensive persons with [14] and without antihypertensive therapy [15-20], in patients with mild hypertension untreated [19, 21, 22] or treated with single doses of antihypertensive agents [23, 24], and in hypertensive persons whose blood pressure had been controlled by drug therapy [21, 25-39]. However, several well-designed studies have failed to show any effect of NSAIDs on blood pressure [40-51]. In addition, many randomized studies [52-63] have attempted to compare the effect of various NSAIDs on blood pressure control with widely differing results that have been thus far inconclusive. For most of the individual trials, the estimates may have been imprecise because the sample size was insufficient. In view of the anticipated increase in the prevalence of hypertension [64] and the substantial use of NSAIDs, any potential drugdrug (NSAID-antihypertensive agent) and drug-disease (NSAID-hypertension) interactions should be fully clarified. Consequently, we did a meta-analysis of randomized trials. Our primary goal was to produce a stable estimate of the overall effect of various NSAIDs on blood pressure; our secondary aims were to evaluate possible mechanisms by which NSAID therapy may alter blood pressure and to determine potential predisposing factors for this interaction. It has been proposed that NSAIDs may alter blood pressure through the effects of prostaglandin synthesis inhibition on body weight, cardiac output, or renal function. Consequently, where provided, we have included these data in the meta-analysis. Although NSAIDs have been associated with blood pressure elevation in normotensive persons and in both treated and untreated hypertensive persons, data pertaining to studies including persons in these subgroups were also analyzed separately to determine whether differential effects occurred in various population groups. Similarly, it was uncertain whether NSAIDs interacted with antihypertensive agents from different classes in the same manner and whether different NSAIDs altered blood pressure to the same degree. Consequently, we also studied these subgroups separately. Methods We did a MEDLINE search from 1966 to 1990. We also did the following additional searches: Embase (1974 to 1990), Biosis (1969 to 1990), Diogenes (1976 to 1990), Science Citation Abstracts (1972 to 1990), International Pharmaceutical Abstracts (1970 to 1990), IOWA Drug Information Service (1966 to 1990), and the Combined Health Information Database (1973 to 1990). For each search, key words relating to trial design (meta-analysis, research design, double-blind method, double-blind study, double, blind, random allocation, random, control, clinical trials) were crossed with the names of individual NSAIDs and the following terms: anti-inflammatory agents, nonsteroidal, hypertension, blood pressure. Articles reviewing the potential interaction between NSAIDs and blood pressure were selected from these searches, and their bibliographies were carefully checked for randomized trials not published elsewhere. We also reviewed textbooks on hypertension, clinical pharmacology, and NSAIDs, and checked reference lists of all randomized trials identified by any of the above means. We selected 194 articles as potentially fulfilling the entry criteria. Only 60 articles, however, described random allocation of one or more NSAIDs and measurement of the effect of NSAIDs on blood pressure. Of the 60 articles, 38 included randomized and controlled trials [14-51] (Appendix Tables 1 and 2). Twelve more articles [52-63] were reports of randomized but not placebo-controlled studies; in these studies, two or more NSAIDs were compared with each other rather than with placebo in terms of their effects on blood pressure control. The remaining 10 articles [65-74] could not be included: eight articles [65-72] because they did not provide measures of variance for the blood pressure data such as standard error or standard deviation, which was needed for our analysis; one article [73] because no blood pressure data were provided; and one article [74] because blood pressure measurement was not the primary goal of the study and because uncontrolled administration of morphine in that trial probably confounded blood pressure levels. The eight articles that did not provide variance data for the blood pressure measurements [65-72] and the article in which blood pressure data were not provided [73] were similar to the 50 articles included in the meta-analysis with respect to patient characteristics, relevant diagnoses, and treatment received. In addition, like the included trials, reporting of an effect of NSAIDs on blood pressure was inconsistent among these articles. However, many were completed several years ago, reducing the possibility of obtaining accurate, reliable data from the original authors; most were abstracts [66, 67, 69, 70, 73], and none had a large sample size with adequate follow-up. Consequently, we considered it appropriate to exclude these studies. Control and Measurement of Potential Bias To minimize selection bias, the Clinical Trials Coordinator coded the methods and results of articles that potentially fulfilled the entry criteria for the meta-analysis. The relevant methods and results sections were photocopied after any identifying information was blacked out. The decision to accept or reject articles was made by two authors, based on the methods alone without any knowledge of the source of the articles (authors or institution) and achieved by consensus. The same two authors subsequently developed an algorithm for assessing the methodologic rigor and scientific quality of the articles to be pooled and for calculating quality assessment scores (0 to 100 [the higher the score, the better the quality of the study assessed]), using only the methods and results sections. This algorithm was broadly based on a systematic evaluation of study quality published by Chalmers and colleagues [75]. Quality assessment scores by the two assessors highly correlated (r = 0.9), suggesting close interobserver agreement. In an attempt to control data-extraction bias, relevant data were drawn from papers by the assessors, who were blinded to all but the results sections, and in 89% of studies evaluated agreement in the data extracted was complete. One author provided a quality assessment score for all trials and extracted data from every trial included in the meta-analysis, whereas the other author reviewed a 20% random selection for quality assessment scoring and another 20% random selection for extraction of data. Appendix Tables 1 and 2 present the relevant features of all randomized, controlled trials with a placebo group. Table 1 provides details of patients at trial entry (age, sex, race) and key study features (sample size, percent dropouts, design, quality assessment score, geographic location, and source of support). Appendix Table 4 outlines the treatment received by patients in each trial (including diet, NSAID type and duration of use, and antihypertensive type and duration), and the average difference (in mm Hg) between mean blood pressure recorded on NSAID treatment and control treatment, respectively, adjusted for baseline mean blood pressure ([NSAID treatment mean blood pressure -baseline mean blood pressure] [control treatment mean blood pressure baseline mean blood pressure]). Appendix Tables 3 and 4 present similar information for randomized, controlled trials without a placebo group. Because only two trials [41, 51] used ambulatory blood pressure monitoring (both with same small sample sizes: n = 12) and all other trials assessed blood pressure using standardized mercury sphygmomanometers, the method of blood pressure measurement was not considered in the analysis. Table 1. Meta-analysis of Randomized, Placebo-Controlled Trials Appendix Table 1. Study Features of Randomized, Controlled Trials *Table OMITTED Appendix Table 2. Treatment Received in Randomized, Controlled Trials *Table OMITTED Appendix Table 3. Study Features of Randomized Trials without a Placebo Group *Table OMITTED Appendix Table 4. Treatment Received in Randomized Trials without a Placebo Group *Table OMITTED Combining the Trials The randomized, controlled trials assessing the effect of NSAIDs on blood pressure [14-51] may be readily subdivided into two broad categories (Appendix Table 3): those of predominantly white, middle-aged patients of both sexes with mild to moderate uncomplicated essential hypertension [29 trials] and those of predominantly white, healthy, young volunteers of both sexes with no history of hypertension and with normal blood pressure (15 trials). These broad categories may be further subdivided (Appendix Tables 1 and 2) into three groups of trials in hypertensive patients and two groups of trials involving normal volunteers based on whether or not antihypertensive therapy was coadministered and on its duration. Because all these trials were randomized and controlled, measured the effect of NSAIDs on blood pressure in patients with uncomplicated mild to moderate essential hypertension or healthy volunteers, and had no other apparent systematic differences between the trials in each of the five groups, we considered it clinically appropriate to pool their results. To assess whether these trials could be combined statistically, the randomized, contro

Clinical Pharmacokinetics of Metformin

Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine.Metformin is excreted unchanged in urine. The elimination half-life (t1/2) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CLR) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CLR and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CLCR). AS the CLR and CL/F decrease approximately in proportion to CLCR, the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CLCR.The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin.Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.

Health-Related Quality of Life and Tamoxifen in Breast Cancer Prevention: A Report From the National Surgical Adjuvant Breast and Bowel Project P-1 Study

PURPOSE This is the initial report from the health-related quality of life (HRQL) component of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. This report provides an overview of HRQL findings, comparing tamoxifen and placebo groups, and advice to clinicians counseling women about the use of tamoxifen in a prevention setting. PATIENTS AND METHODS This report covers the baseline and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months of the study. Findings are presented from the Center for Epidemiological Studies-Depression Scale (CES-D), the Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF-36) and sexual functioning scale, and a symptom checklist. RESULTS No differences were found between placebo and tamoxifen groups for the proportion of participants scoring above a clinically significant level on the CES-D. No differences were found between groups for the MOS SF-36 summary physical and mental scores. The mean number of symptoms reported was consistently higher in the tamoxifen group and was associated with vasomotor and gynecologic symptoms. Significant increases were found in the proportion of women on tamoxifen reporting problems of sexual functioning at a definite or serious level, although overall rates of sexual activity remained similar. CONCLUSION Women need to be informed of the increased frequency of vasomotor and gynecologic symptoms and problems of sexual functioning associated with tamoxifen use. Weight gain and depression, two clinical problems anecdotally associated with tamoxifen treatment, were not increased in frequency in this trial in healthy women, which is good news that also needs to be communicated.

Stereoselective disposition of ibuprofen enantiomers in infants

The pharmacokinetics of the enantiomers of ibuprofen were investigated after oral administration of a single 7.6 +/- 0.3 mg kg-1 dose of the racemate in 11 infants. Mean (+/- s.d.) half-lives were 1.6 +/- 0.5 h for S(+) and 1.5 +/- 0.5 h for R(-) and mean (+/- s.d.) AUC values were 31.5 +/- 14.3 mg l-1 h for S(+) and 36.6 +/- 13.8 mg l-1 h for R(-). Since plasma concentrations of the active S(+)-isomer were lower than those reported in adults, a higher dosage might be required in infants.

The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings

Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA.

Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials.

Objective To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee. Design Systematic review and meta-analysis. Data sources Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014. Eligibility criteria for selecting studies Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee. Data extraction Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration’s tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions. Results 12 reports (13 randomised trials) were included. There was “high quality” evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference −0.5, 95% confidence interval −2.9 to 1.9) and disability (0.4, −1.7 to 2.5) or improving quality of life (0.4, −0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was “high quality” evidence that paracetamol provides a significant, although not clinically important, effect on pain (−3.7, −5.5 to −1.9) and disability (−2.9, −4.9 to −0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. “High quality” evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain. Conclusions Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines. Systematic review registration PROSPERO registration number CRD42013006367.

Assessment of diclofenac or spinal manipulative therapy, or both, in addition to recommended first-line treatment for acute low back pain: a randomised controlled trial

BACKGROUND We aimed to investigate whether the addition of non-steroidal anti-inflammatory drugs or spinal manipulative therapy, or both, would result in faster recovery for patients with acute low back pain receiving recommended first-line care. METHODS 240 patients with acute low back pain who had seen their general practitioner and had been given advice and paracetamol were randomly allocated to one of four groups in our community-based study: diclofenac 50 mg twice daily and placebo manipulative therapy (n=60); spinal manipulative therapy and placebo drug (n=60); diclofenac 50 mg twice daily and spinal manipulative therapy (n=60); or double placebo (n=60). The primary outcome was days to recovery from pain assessed by survival curves (log-rank test) in an intention-to-treat analysis. This trial was registered with the Australian Clinical Trials Registry, ACTRN012605000036617. FINDINGS Neither diclofenac nor spinal manipulative therapy appreciably reduced the number of days until recovery compared with placebo drug or placebo manipulative therapy (diclofenac hazard ratio 1.09, 95% CI 0.84-1.42, p=0.516; spinal manipulative therapy hazard ratio 1.01, 95% CI 0.77-1.31, p=0.955). 237 patients (99%) either recovered or were censored 12 weeks after randomisation. 22 patients had possible adverse reactions including gastrointestinal disturbances, dizziness, and heart palpitations. Half of these patients were in the active diclofenac group, the other half were taking placebo. One patient taking active diclofenac had a suspected hypersensitivity reaction and ceased treatment. INTERPRETATION Patients with acute low back pain receiving recommended first-line care do not recover more quickly with the addition of diclofenac or spinal manipulative therapy.

CareTrack: Assessing the appropriateness of health care delivery in Australia

Objective: To determine the percentage of health care encounters at which a sample of adult Australians received appropriate care (ie, care in line with evidence‐based or consensus‐based guidelines).

A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients?

Benzbromarone, a potent uricosuric drug, was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthélabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world, and increased difficulty in accessing it in other countries where it has never been available.The overall aim of this paper is to determine if the withdrawal of benzbromarone was in the best interests of gouty patients and to present a benefit-risk assessment of benzbromarone. To determine this, we examined (i) the clinical benefits associated with benzbromarone treatment and compared them with the success of alternative therapies such as allopurinol and probenecid, particularly in patients with renal impairment; (ii) the attribution of the reported cases of hepatotoxicity to treatment with benzbromarone; (iii) the incidence of hepatotoxicity possibly due to benzbromarone; (iv) adverse reactions to allopurinol and probenecid. From these analyses, we present recommendations on the use of benzbromarone.Large reductions in plasma urate concentrations in patients with hyperuricaemia are achieved with benzbromarone and most patients normalize their plasma urate. The half-life of benzbromarone is generally short (about 3 hours); however, a uricosuric metabolite, 6-hydroxybenzbromarone, has a much longer half-life (up to 30 hours) and is the major species responsible for the uricosuric activity of benzbromarone, although its metabolism by cytochrome P450 (CYP) 2C9 in the liver may vary between patients as a result of polymorphisms in this enzyme. It is effective in patients with moderate renal impairment. Standard dosages of benzbromarone (100 mg/day) tend to produce greater hypouricaemic effects than standard doses of allopourinol (300 mg/day) or probenecid (1000 mg/ day).Adverse effects associated with benzbromarone are relatively infrequent, but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from the literature. Eleven cases have been reported by Sanofi-Synthélabo, but details are not available in the public domain. Only one of the four published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three cases lacked incontrovertible evidence to support a diagnosis of benzbromarone-induced hepatotoxicity. If all the reported cases are assumed to be due to benzbromarone, the estimated risk of hepatotoxicity in Europe was approximately 1 in 17 000 patients but may be higher in Japan.Benzbromarone is also an inhibitor of CYP2C9 and so may be involved in drug interactions with drugs dependent on this enzyme for clearance, such as warfarin. Alternative drugs to benzbromarone have significant adverse reactions. Allopurinol is associated with rare life-threatening hypersensitivity syndromes; the risk of these reactions is approximately 1 in 56 000. Rash occurs in approximately 2% of patients taking allopurinol and usually leads to cessation of prescription of the drug. Probenecid has also been associated with life-threatening reactions in a very small number of case reports, but it frequently interacts with many renally excreted drugs. Febuxostat is a new xanthine oxidoreductase inhibitor, which is still in clinical trials, but abnormal liver function is the most commonly reported adverse reaction.Even assuming a causal relationship between benzbromarone and hepatotoxicity in the identified cases, benefit-risk assessment based on total exposure to the drug does not support the decision by the drug company to withdraw benzbromarone from the market given the paucity of alternative options. It is likely that the risks of hepatotoxicity could be ameliorated by employing a graded dosage increase, together with regular monitoring of liver function. Determination of CYP2C9 status and consideration of potential interactions through inhibition of this enzyme should be considered. The case for wider and easier availability of benzbromarone for treating selected cases of gout is compelling, particularly for patients in whom allopurinol produces insufficient response or toxicity.We conclude that the withdrawal of benzbromarone was not in the best interest of patients with gout.