Reduced Incidence of Stroke in Patients with Gout Using Benzbromarone

Gout is strongly associated with the incidence of atherosclerotic events, including stroke and myocardial infarction. Considering the increased prevalence of stroke in the population with gout, the aim of this study was to evaluate the effects of benzbromarone, a uricosuric agent, on the incidence of stroke in the population with gout. We used data from the Taiwanese National Health Insurance Registration Database (NHIRD). The benzbromarone user cohort included 15,143 patients; each patient was age- and sex-matched with one non-user randomly selected from the population with gout. Cox proportional hazard regression analysis was conducted to estimate the effects of benzbromarone on the incidence of stroke in the population with gout. The incidence of stroke was significantly lower in benzbromarone users than in benzbromarone non-users. The HR for the incidence of stroke was lower in male benzbromarone users than in non-users. An analysis of three age groups (<40, 40–59, and ≥60 years) indicated that the HRs in those aged 40–59 years and ≥60 years were significantly lower among benzbromarone users than non-users. In the population with gout, the incidence of stroke was lower in benzbromarone users than in benzbromarone non-users.

Sex differences in response to allopurinol and benzbromarone in gout: a retrospective cohort study

Objective Owing to lower mean uric acid excretion in women compared with men, uricosuric agents might be preferred in women over xanthine oxidase (XO) inhibitors. We therefore investigated the differences in response to two urate-lowering therapies (ULTs) with different modes of action within and between sexes. Methods This retrospective cohort study included patients with a clinical diagnosis of gout who started allopurinol and/or benzbromarone. The successful response to ULT, defined as reaching a serum uric acid (sUA) target of &lt;0.36 mmol/l within 6 months after commencing ULT, was compared between allopurinol and benzbromarone in women and men. Effect modification by sex on differences in response was evaluated. Results Allopurinol was started in 255 women and 1045 men, and benzbromarone in 60 women and 205 men. After 6 months, the proportions of women reaching the sUA target were 58.4% and 66.7% for allopurinol and benzbromarone, respectively (difference, −8%; 95% CI: −22%, 5%). The respective proportions in men were 61.0% and 75.6%, respectively (difference, −15%; 95% CI: −21%, −8%). Corrected for confounding, the odds ratio (OR) of reaching the target on benzbromarone vs allopurinol within women was 0.91 (95% CI: 0.47, 1.75), and within men 1.55 (95% CI: 1.04, 2.32). Corrected for confounding, sex was not an effect modifier of the difference in allopurinol and benzbromarone response (OR, 0.59; 95% CI: 0.28, 1.24). Conclusion This study did not demonstrate between-sex differences regarding the response to either a uricosuric agent or an XO inhibitor, negating different treatment choices by sex.

Impact of urate-lowering drugs on the progression and recovery from chronic kidney disease among gout patients

Background This study investigates the association between exposure to urate-lowering drugs (ULDs) and progression and recovery from chronic kidney disease (CKD). Methods We identified 5860 incident gout patients at Chang Gung Memorial Hospital from 2012 to 2015. Propensity score (PS)-weighted Cox proportional hazards model was used to estimate hazard ratios (HRs) for CKD progression and improvement. A separate analysis was conducted to assess the HR for CKD progression and CKD recovery among those with worsening CKD. Results The incidence of CKD progression among allopurinol, febuxostat and uricosuric agent users were 1.98, 1.88 and 1.64 per 1000 person-days. Compared with allopurinol users, the PS-weighted HR (95% confidence intervals [CIs]) was 1.77 (0.85–1.76) for febuxostat users and 1.37 (0.71–1.37) for uricosuric agent users for CKD progression and 1.43 (1.26–1.62) for febuxostat users and 1.00 (0.88–1.14) for uricosuric agent users for CKD improvement. Compared to allopurinol users, the HRs for CKD progression were 1.14 (0.80–1.66) for febuxostat users and 0.92 (0.67–1.31) for uricosuric agent users. Among 741 patients who had CKD progression, the incidence of CKD recovery was 1.33, 6.21 and 3.53 per 1000 person-days for allopurinol, febuxostat and uricosuric agent users. The HRs (95% CIs) for recovery in febuxostat and uricosuric agent users were 2.17 (1.40–3.47) and 1.80 (1.20–2.83) compared to allopurinol users. Conclusions CKD progression and recovery are common in gout patients using ULDs. Febuxostat and benzbromarone were associated with a similar risk of CKD progression with allopurinol, which has a poorer recovery compared with other ULDs.

Pharmacological Review on Uricosuric activity

The naturally available uricosuric agents are Tinospora cardifolia, Allium sepa, Cajanus Cajan, Piper nigrum etc., Natural medicinal plants having no side effects are more preferred when compared to synthetic medications. Uricosuric agents increase the urinary excretion of uric acid hence the natural uricosuric agent is preferred to prevent many diseases like gout, arthritis, kidney stones etc., without side effect. Uricosuric medications are the substances that increase the excretion of uric acid in urine, thus reducing the concentration of uric acid in blood plasma. Prolonged and untreated hyperuricemia results into gout, a severe inflammatory condition. Sustain hyperuricemia leads to impaired blood pressure control, renal impairment and nephropathy. The common factors for deposition of uric acid in blood are drinking alcohol and taking high purine diet. The various screening methods for the uricosuric activity are uricosuric activity in mice, Potassium oxonate induced activity, and Phenol red excretion methods are explained in this review.

Abstract 325: Probenecid Downregulates Kidney Pendrin and AQP-2 and Potentiates Hydrochlorothiazide Diuresis

Background: Concurrent inactivation of the kidney Na-Cl co-transporter NCC and the Cl - /HCO 3 - exchanger pendrin leads to significant salt wasting, whereas single deletion of NCC does not cause any significant salt wasting, indicating that pendrin mitigates the salt excretion caused by NCC inactivation. Probenecid is a uricosuric agent that, in addition, exhibits positive ionotropic effect in the heart and inhibits pendrin in the kidney. Hypothesis: Pretreatment with probenecid will inactivate/downregulate pendrin; therefore, leaving NCC as the main salt absorbing transporter in the distal nephron, and hence enhancing the hydrochlorothiazide (HCTZ) diuresis. Results: Male Sprague Dawley rats were treated with probenecid intraperitoneally (IP) at 250 or 100 mg/kg for 6 days and then received HCTZ while being maintained on probenecid for 4 more days. Urine output increased from 9.8 at baseline to 15.9 ml/24 hrs after 10 days of Probenecid at 250 mg/kg (p<0.01, n=5). Treatment with HCTZ alone for 4 days caused a mild diuresis, with urine output increasing to 13.8 ml/24 hrs (p>0.05, vs. baseline, n=5). However, rats pretreated with Probenecid for 6 days exhibited a profound diuresis when HCTZ was added for 4 additional days, with urine output increasing to 42.9 ml/day, a more than 300% increase vs. rats treated with either Probenecid or HCTZ (p<0.003 vs. both groups, n = 5). In the absence of pretreatment with Probenecid, the diuresis caused by concurrent Probencid plus HCTZ treatment was not different vs. HCTZ alone (p>0.05). Immunofluorescent, Northern and/or Western hybridization studies demonstrated a significant reduction in the expression of pendrin and AQP2 in kidneys of probenecid treated rats. At 100 mg/kg, Probenecid alone had no significant effect on urine output but caused a robust diuresis when HCTZ was added, with the urine output increasing from 9.93 baseline to 24.23 (p<0.001, n=7). Conclusion: Probenecid pretreatment downregulates pendrin and AQP2 and robustly enhances diuresis by HCTZ-mediated NCC inhibition in the kidney distal nephron. We propose that the combination of Probenecid and a thiazide derivative offers a powerful diuretic regimen for the treatment of fluid overloaded states such as CHF.