Allopurinol Group Research Articles

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Comparison of benzbromarone and allopurinol on the risk of chronic kidney disease in people with asymptomatic hyperuricemia

ObjectiveThe objective of the study was to compare the relative effects of benzbromarone and allopurinol on the risk of developing chronic kidney disease in persons with asymptomatic hyperuricemia. MethodsA retrospective cohort study was conducted to analyze a 2003–2015 national database including all claims data of 2 million beneficiaries in Taiwan. Asymptomatic hyperuricemia was defined as follows: persons using urate-lowering drugs who never developed gout flares. The benzbromarone group included persons ages 20–84 that had asymptomatic hyperuricemia and received benzbromarone alone. The allopurinol group included persons ages 20–84 that had asymptomatic hyperuricemia and received allopurinol alone. The maximum follow-up time was set as 5 years in this study. The main outcome was defined as follows: persons were newly diagnosed with chronic kidney disease. A Cox proportional hazards regression analysis was performed to test the association between variables and the risk of chronic kidney disease. ResultsAfter propensity score matching, 9107 persons in the benzbromarone group and 4554 persons in the allopurinol group were eligible for the study. Approximately 71% of the study subjects were males. The mean age was 56 years old. The incidence rate of chronic kidney disease was lower in the benzbromarone group than in the allopurinol group (1.18 versus 1.99/per 100 person-years, incidence ratio = 0.60, and 95% confidence interval = 0.52–0.68).The Cox proportional hazards regression analysis disclosed that after adjusting for co-variables, there was a decreased risk of developing chronic kidney disease in the benzbromarone group as compared with the allopurinol group (hazard ratio = 0.59, 95% confidence interval = 0.52–0.67 and P<0.001). ConclusionsThe use of benzbromarone is associated with a lower hazard of developing chronic kidney disease as compared to allopurinol use among persons ages 20–84 with asymptomatic hyperuricemia. More studies are needed to confirm our findings.

The Anti-hyperuricemia and Anti-inflammatory Effects of Atractylodes Macrocephala in Hyperuricemia and Gouty Arthritis Rat Models.

Atractylodes macrocephala is a traditional Chinese medicine with a variety of pharmacological activities. This study aimed to evaluate its anti-hyperuricemia and antiinflammatory effects on gout, and to preliminarily explore its mechanism. The hyperuricemia rat model was established by intraperitoneal injection of oteracil potassium and intragastric gavage of yeast powder solution. And the acute gouty arthritis (GA) model was established by injecting monosodium urate (MSU) suspension. In the study of the antihyperuricemia effect of Atractylodes macrocephala, the healthy male Sprague-Dawley rats were randomly divided into the blank group, hyperuricemia group allopurinol group as well as low, moderate and high dose groups of Atractylodes macrocephala decoction (N=8 rats in each group). Serum, liver and kidney tissue samples were collected from each group. Serum uric acid (UA), adenosine deaminase (ADA) and xanthine oxidase (XOD) levels in each group were detected by enzyme-linked immunosorbent assay (ELISA). Protein levels of ADA and XOD in liver tissues were detected by Western blot, and renal histological changes were observed by Hematoxylin-eosin (H&E) and Masson staining. In order to investigate the anti-inflammatory effect of Atractylodes macrocephala, the healthy male Sprague-Dawley rats were randomly divided into the blank group, GA group, colchicine group, high, moderate and low dose groups of Atractylodes macrocephala decoction (N=8 rats in each group), and serum and synovial tissue of each group were collected. Then the level of serum interleukin (IL)-1β and tumor necrosis factor (TNF)-α was observed by ELISA, and the histological changes of synovial tissue were observed by H&E staining. Besides, the expression of adenosine monophosphate- activated protein kinase (AMPK) /silent information regulator (SIRT) 1/ nuclear factor kappa B (NF-κB) protein in synovial tissue was observed by Western blot and immunohistochemistry. The markers of M1 and M2 macrophages, inducible nitric oxide synthase (iNOS) and arginase-1 (ARG1) were observed by Western blot and immunofluorescence. Atractylodes macrocephala could reduce the production of UA by inhibiting the level of ADA and XOD, and could improve renal injury and fibrosis. In addition, Atractylodes macrophages could reduce the levels of IL-1β and TNF-α, activate AMPK/SIRT1 signaling pathway, and inhibit the activation of NF-κB and the polarization of macrophages to a pro-inflammatory phenotype. Atractylodes macrocephala shows good anti-hyperuricemic and anti-inflammatory effects, and its anti-inflammation pharmacological activity may be related to the inhibition of M1 macrophage polarization and NF-κB activation through activating AMPK/SIRT1.

EFFECT OF GIVING GARLIC ON URIC ACID LEVELS OF HYPERURISEMIC WHITE RATS (Rattus norvegicus)

Hyperuricemia is a condition where uric acid levels in the body exceed normal limits due to an increase in excessive purine synthesis in the body due to unhealthy eating patterns, the process of excreting uric acid from the body is disrupted or a combination of both. Black garlic contains s-allyl cysteine ​​(SAC), tetrahydro-β-carbolines, alkaloids, and flavonoids which are thought to inhibit the action of the xanthine oxidase enzyme so that it can reduce uric acid. The short-term aim of this study was to determine the effect of black garlic on uric acid levels in hyperuricemic white rats. The long-term goal to be achieved is the use of black garlic to prevent and or overcome the negative effects of hyperuricemia. Rats were grouped into five groups: positive control (A), allopurinol group (B), garlic group at doses of 240 mg (C), 480 mg (D) and 960 mg (E). Induction of hyperuricemia was carried out by injection of potassium oxonate and addition of cow brains for 14 days, followed by treatment. The average yield of uric acid in each group was A: 15.02 ± 0.71, B: 6.45 ± 0.13, C: 8.46 ± 0.12, D: 7.64 ± 0.14, E: 7.55 ± 0.55. Data were analyzed using One Way ANOVA followed by Post Hoc LSD. In conclusion, by giving various doses of black garlic can reduce uric acid levels in hyperuricemia rats.

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial.

People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference-0.17, 95% CI-0.52 to 0.17, p=0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. The British Heart Foundation and the UK Stroke Association.

Impact of Allopurinol Pretreatment on Coronary Blood Flow and Revascularization Outcomes after Percutaneous Coronary Intervention in Acute STEMI Patients: A Randomized Double Blind Clinical Trial.

The generation of reactive oxygen species, which is induced by the activation of the xanthine oxidase (XO) enzymatic system, is one of the primary causes of ischemia-reperfusion injury for an ischemic heart. Allopurinol, as an XO inhibitor, plays an inhibitory role in free radical production in ST-elevation myocardial infarction (STEMI) patients. The aim of this study is to evaluate the impact of allopurinol pre-treatment on post-revascularization outcomes in patients admitted with STEMI. Ninety patients with acute STEMI were enrolled in this randomized double-blind clinical trial and divided into two equal groups. The allopurinol group received a 600 mg allopurinol loading dose before the emergency PCI, and the control group received a placebo medication of the same shape. Thrombolysis in Myocardial Infarction (TIMI) flow, ECG changes, troponin level, and the occurrence of major cardiac events (MACE) during a 1-month follow-up were assessed. In the end, 81 patients were analyzed. The mean age of the patients was 59.52(11.31) and 61.3(9.25) in the allopurinol and control groups, respectively (p = 0.49). The troponin level 48 hours after the PCI and ST-elevation regression showed no significant difference between the groups [(p = 0.25) and (p = 0.21), respectively]. TIMI flow had improved in the allopurinol group compared to the placebo (p = 0.02). The PCI success rate was 78.6% and 61.5% in the case and control groups, respectively (p = 0.09). MACE and other clinical outcomes were similar between the groups (p > 0.05). This study revealed that allopurinol pre-treatment could improve TIMI flow in patients undergoing primary or rescue PCI in an acute STEMI setting.

Effect of Febuxostat versus Allopurinol on the Glomerular Filtration Rate and Hyperuricemia in Patients with Chronic Kidney Disease.

Hyperuricemia is a risk factor for the progression of chronic kidney disease (CKD). We compared febuxostat versus allopurinol in the progression of CKD and hyperuricemia in 101 patients with Stage 3-4 CKD treated with febuxostat or allopurinol for at least 6 months for hyperuricemia (>7 mg/dL) between January 2012 and December 2016. Baseline characteristics, serum uric acid (SUA), serum creatinine, and estimated glomerular filtration rate (eGFR) at entry and 6 months were compared. The primary outcome was the decline in eGFR and the secondary outcomes were reductions in SUA and adverse events. Fifty-four were in the febuxostat group and 47 were in the allopurinol group. The baseline characteristics were comparable except for age. The mean dose of febuxostat and allopurinol was 43.70 ± 14.5 mg and 108.51 ± 40 mg, respectively. After 6 months, the median rate of decline in eGFR was 1.2 mL/min/1.73 m2 (IQR: 1.2, 5.5) in the febuxostat group and 3.1 mL/min/1.73 m2 (0.6, 6.2) in the allopurinol group, but this was not statistically significant (P = 0.136). The mean reduction in SUA was significantly better (P = 0.004) in the febuxostat group (3.9 ± 1.7 mg/dL) compared with the allopurinol group (2.1 ± 1.0 mg/dL). Both drugs had no serious adverse events. Febuxostat was better at reducing hyperuricemia than allopurinol, but there was no significant difference in the progression of CKD. Large randomized trials and long-term follow-up are necessary to see whether febuxostat has a favorable effect on the progression of CKD.

The effect of allopurinol on serum uric acid levels in patients with diabetic nephropathy; a systematic review and meta-analysis on randomized clinical trials

Introduction: The correlation between hyperuricemia and chronic kidney disease (CKD) is an approval issue; this study aimed to evaluate the effect of allopurinol on serum uric acid levels in patients with diabetic nephropathy, with the review of randomized clinical trials (RCTs). Materials and Methods: This meta-analysis study was conducted on RCTs in diabetic nephropathy patients, which evaluated the effect of allopurinol on serum uric acid levels. Data were collected by searching international databases and Google Scholar search engines until May 2023. STATA 14 software and the random effects model were conducted to analyze the data. A P value less than 0.05 was considered significant. Results: In this study, five studies with a sample size of 942 patients were assessed. The effect of allopurinol on serum uric acid in comparison to the placebo group deduced that the standard mean difference between the allopurinol group and placebo group was -1.55 mg/dL, which was statistically significant (CI: -2.07 to -1.02). Conclusion: Allopurinol through its uric acid lowering effect would be beneficial for patients with diabetic nephropathy in preventing the progression of CKD. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO website (ID: CRD42023412051).

THE THERAPEUTIC EFFECT OF ALLOPURINOL IN FATTY LIVER DISEASE IN RATS.

Hyperuricemia is associated with non-alcoholic fatty liver disease (NAFLD). We therefore aimed at evaluating the influence of allopurinol on the course of NAFLD in rats. We divided 21 mature albino Sprague Dawley rats into three groups: controls (n = 7, normal diet for 12 weeks); NAFLD rat models (by feeding water containing 30% fructose for first 8 weeks) treated with allopurinol subsequently for the next 4 weeks (n = 7); and similar case treated with placebo (saline) subsequently for the next 4 weeks (n = 7). We compared the histopathological scores, IL-1 and IL-2 immunoexpression levels across the groups. Liver histopathological score was determined by observing the steatosis (the percentage of liver cells containing fat): <25% = 1+, 25% - 50% = 2+, 51% - 75% = 3+, >75% = 4+; inflammation and necrosis: 1 focus per low-power field = 1+; and 2 or more foci = 2+. The number of liver IL-1 and IL-2 positive cells was measured by systematically scoring at least 100 hepatocyte cells per field in 10 fields of tissue sections by a magnification of 100. Xanthine oxidase (XO) activity and lipid peroxidation was significantly different in the allopurinol group compared to the saline group (XO; 0.098 ± 0.006 mU/mg vs. 0.162 ± 0.008 mU/mg, p = 0.01, 0.116 ± 0.040 nmol malondialdehyde/mg versus 0.246 ± 0.040 nmol malondialdehyde /mg, p = 0.01). The allopurinol group had lower histopathological scores, IL-1 and IL-2 immunoexpression levels in the liver compared to the saline group (2.13 ± 0.35 against 5.45 ± 0.24, p = 0.003, IL-1; 5.76 ± 0.43 against 12.85 ± 3.26, p = 0.023, IL-2; 8.55 ± 1.14 against 56.23 ± 7.12, p = 0.002). Allopurinol has a therapeutic role against the progression of NAFLD of the rats.

Risk of Erectile Dysfunction in Male Patients with Gout Treated with Febuxostat or Allopurinol: A Propensity Score-Matched Cohort Study.

To evaluate and compare the risk of erectile dysfunction (ED) associated with the use of allopurinol and febuxostat in adult male gout patients. We conducted a cohort study using TriNetX (Cambridge, MA, USA), a global federated health research network that provides real-time electronic medical record datasets. We analyzed and compared the associated risk of ED in gout patients who started taking allopurinol or febuxostat within 12 months. Propensity score matching was performed to adjust for demographic variables, comorbidities, and medication use. Kaplan-Meier analysis was used to estimate the probability of the outcome of interest. The hazard ratio (HR) and associated confidence intervals were calculated along with the proportionality test using R's Survival Package v3.2-3. We identified 679,862 patients with gout among 107,517,445 patients in the database. Of these patients, 24,000 were treated with febuxostat and 299,726 with allopurinol. After propensity matching, 9075 patients receiving febuxostat without allopurinol (febuxostat group) and 9075 corresponding patients receiving allopurinol without febuxostat (allopurinol group) were analyzed for comparison. Among all male patients over 19 years of age, febuxostat was associated with a significantly higher risk of ED versus allopurinol (HR 1.354; 95% confidence interval (CI) 1.003-1.829; log rank test, p = 0.047). After subgroup analysis, in gout patients aged 19-64 years, a significantly higher incidence of ED was observed in the febuxostat group than in the allopurinol group (HR 2.002, 95% CI 1.282-3.126). The risk of ED did not differ significantly between the allopurinol and febuxostat groups in gout patients older than 65 years. Febuxostat may be associated with a higher risk of ED than allopurinol in adult male patients with gout. Future large-scale prospective studies are warranted to confirm our results.

Effects of Allopurinol as a xanthine oxidase inhibitor on depressive-like behavior of rats and changes in serum BDNF level.

Depression is a psychiatric disorder characterized by low mood and loss of interest in daily activities. Allopurinol, a xanthine oxidase blocker, is widely administered for the treatment of hyperuricemia. Recently, its effects on serotonin and depressive like behaviors have been reported. On the other hand, the level of brain-derived neurotrophic factor (BDNF), a protective and regenerative neurotrophic, has been increased by many antidepressants. The purpose of this study was to evaluate the antidepressant effects of allopurinol and changes in serum level of BDNF compared to those of fluoxetine. Thirty-five male Wistar albino rats divided into five groups (control, 10mg/kg fluoxetine, 25, 50 and 100mg/kg allopurinol; n=7 per group), that received all treatments intraperitoneally, every day. Forced swimming tests (FST), tail suspension test (TST) and open field test (OFT) were performed after 21 days of drug administration. Finally, the serum BDNF levels were measured using the sandwich ELISA method. All doses of allopurinol and fluoxetine reduced the duration of immobility time in FST and TST. No significant changes were observed in the number of lines crossed in OFT between either allopurinol or fluoxetine groups and control group. Serum level of BDNF were significantly higher in fluoxetine and allopurinol 50 and 100mg/kg groups. Long-term administration of allopurinol 50 and 100mg/kg have shown antidepressant effects in behavioral tests along with an increase in the amount of serum BDNF concentration. The OFT results suggested that allopurinol did not have any significant effects on motor activity. The increased serum level of the BDNF in the allopurinol group was correlated with FST and TST results. However, it is still not clear whether the antidepressant effects of allopurinol are due to a direct effects on serotonin and/or BDNF or an indirect effect related to its xanthin oxidase inhibition.

Integration of network pharmacology and intestinal flora to investigate the mechanism of action of Chinese herbal Cichorium intybus formula in attenuating adenine and ethambutol hydrochloride-induced hyperuricemic nephropathy in rats

Context Cichorium intybus L. (Asteraceae) formula (CF) has been applied as a folk medicine to treat hyperuricemic nephropathy (HN). However, the exact mechanism remains unclear. Objective To explore the therapeutic effect and mechanism of CF on HN. Materials and methods Through network pharmacological methods, the targets of the active component of CF against HN were obtained. Subsequently, Male Wistar rats were divided into control, HN, allopurinol (50 mg/kg), CF high-dose (8.64 g/kg) and CF low-dose (2.16 g/kg) groups. The HN model was induced via intragastric administration of adenine (100 mg/kg) and ethambutol hydrochloride (250 mg/kg) for 3 weeks. After CF treatment, biochemical indicators including UA, UREA and CREA were measured. Then, HE staining, qRT-PCR and gut microbiota analysis were conducted to further explore the mechanism. Results The network pharmacology identified 83 key targets, 6 core genes and 200 signalling pathways involved in the treatment of HN. Compared to the HN group, CF (8.64 g/kg) significantly reduced the levels of UA, UREA and CREA (from 2.4 to 1.57 μMol/L, from 15.87 to 11.05 mMol/L and from 64.83 to 54.83 μMol/L, respectively), and mitigated renal damage. Furthermore, CF inhibited the expression of IL-6, TP53, TNF and JUN. It also altered the composition of gut microbiota, and ameliorated HN by increasing the relative abundance of some probiotics. Conclusions This work elucidated the therapeutic effect and underlying mechanism by which CF protects against HN from the view of the biodiversity of the intestinal flora, thus providing a scientific basis for the usage of CF.

Low-dose febuxostat exhibits a superior renal-protective effect and non-inferior safety profile compared to allopurinol in chronic kidney disease patients complicated with hyperuricemia: A double-centre, randomized, controlled study.

The present study compared the efficacy and safety of low-dose febuxostat versus allopurinol in chronic kidney disease (CKD) patients complicated with hyperuricemia (HUA). In this double-centre, randomized, controlled study, 120 CKD patients complicated with HUA were recruited and randomly assigned to low-dose febuxostat group (20 mg/day) or allopurinol group (200 mg/day) at 1:1 ratio. The serum creatinine (Scr), serum uric acid (SUA), and estimated glomerular filtration rate (eGFR) were measured at baseline (M0), month (M) 1, M3, and M6. Besides, the drug-related adverse events (AEs) were recorded. The primary outcome was the proportion of patients showing a > 10% decline in eGFR from M0 to M6. The eGFR level was increased at M6, but similar at M0, M1 and M3 in febuxostat group compared with allopurinol group. Notably, the proportion of patients with >10% decline in eGFR from M0 to M6 was decreased in febuxostat group compared with allopurinol group. However, there was no difference of Scr, SUA at M0, M1, M3 and M6 between febuxostat group and allopurinol group. Moreover, there was no difference of drug-related AEs between febuxostat group and allopurinol group. Further subgroup analysis exhibited that low-dose febuxostat presented superior effect on attenuating eGFR decline and lowering SUA level compared with allopurinol in CKD stage 3 subgroup, but not in CKD stage 2 subgroup. Low-dose febuxostat may exhibit a superior renal-protective effect, non-inferior SUA lowering ability and safety profile compared with allopurinol in CKD patients complicated with HUA.

Cardiovascular risk of urate-lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

In the present study, we aimed to investigate the association between urate-lowering drugs and cardiovascular events, primarily focusing on the risk of febuxostat and topiroxostat when compared with allopurinol in Japan. We conducted an observational study with a cohort design using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, including new urate-lowering drugs users between August 1, 2010, and March 31, 2018. Exposure and control groups were defined based on the first prescription of urate-lowering drugs as follows: febuxostat or topiroxostat for exposure groups, allopurinol for the control group, and benzbromarone for the secondary control group. The primary outcome was cardiovascular events, defined as a composite of acute coronary syndrome, cerebral infarction, and cerebral hemorrhage. Hazard ratios were estimated using a Cox proportional hazards model. The number of patients in each exposure and control group was 1,357,671 in the febuxostat group, 83,683 in the topiroxostat group, 1,273,211 in the allopurinol group, and 258,786 in the benzbromarone group. The adjusted hazard ratios for the cardiovascular risk were 0.97 (95% confidence interval [CI]: 0.95-0.98) for febuxostat and 0.84 (95% CI: 0.78-0.90) for topiroxostat groups. The benzbromarone group exhibited similar results. No increased cardiovascular risk was observed with febuxostat or topiroxostat when compared with allopurinol in patients with hyperuricemia in Japan. These results provide real-world evidence regarding the cardiovascular risk associated with urate-lowering drugs, indicating that no additional safety-related regulatory actions are warranted in Japan.

Sulforaphane-driven reprogramming of gut microbiome and metabolome ameliorates the progression of hyperuricemia

IntroductionCurrently, revealing how to prevent and control hyperuricemia has become an essential public health issue. Sulforaphane hasawiderangeofapplications in the management of hyperuricemia. ObjectiveThe study objective was to verify the uric acid-lowering effects and the regulation of the gut-kidney axis mediated by sulforaphane and identify host-microbial co-metabolites in hyperuricemia. MethodsA hyperuricemia model was established by administering feedstuffs with 4% potassium oxonate and 20% yeast. Forty male Sprague–Dawley rats were randomly divided into the normal control, hyperuricemia, allopurinol, and sulforaphane groups. Animals were treated by oral gavage for six consecutive weeks, and then phenotypic parameters, metabolomic profiling, and metagenomicsequencing were performed. ResultsSulforaphane could lower uric acid by decreasing urate synthesis and increasing renal urate excretion in hyperuricemic rats (P＜0.05). We identified succinic acid and oxoglutaric acid as critical host-gut microbiome co-metabolites. Moreover, sulforaphane improved the diversity of microbial ecosystems and functions, as well as metabolic control of the kidney. Notably, sulforaphane exerted its renoprotective effect through epigenetic modification of Nrf2 and interaction between gut microbiota and epigenetic modification in hyperuricemic rats. ConclusionWe revealed that sulforaphane could ameliorate the progression of hyperuricemia by reprogramming the gut microbiome and metabolome. Our findings may provide a good means for efficiently preventing and treating hyperuricemia.

`Risk of cardiovascular disease associated with febuxostat versus allopurinol use in patients with gout: a retrospective cohort study in Korea

Febuxostat is the drug used to treat hyperuricemia in patients with gout. Recently, the usage of Febuxostat has been controversial over the side effects in cardiovascular. The study aimed to comparatively analyze the risk of cardiovascular disease associated with febuxostat and allopurinol use in Korean patients with gout. A cohort study was conducted using national insurance claim data from the Health Insurance Review and Assessment Service (HIRA). Adult patients who were diagnosed with gout and prescribed febuxostat or allopurinol more than once from July 1, 2015, to June 30, 2018 were studied. The outcome was cardiovascular disease. Analysis was performed using Cox’s proportional hazard model following 1:1 propensity score matching to estimate the hazard ratio with a 95% confidence interval. In total, 90,590 patients were defined as the final study cohort who had an average follow-up of 467 days, including 28,732 and 61,858 patients in the febuxostat and allopurinol groups, respectively. After the 1:1 propensity score matching, the risk of cardiovascular disease in the febuxostat group was significantly higher than in the allopurinol group (HR: 1.17; 95% CI: 1.10–1.24). In the sensitivity analysis, the risk of cardiovascular disease in the febuxostat group was significantly higher than in the allopurinol group (HR: 1.09; 95% CI: 1.04–1.15). However, further sensitivity analysis showed no statistically significant difference between the febuxostat group and allopurinol group after adjusting for cardiovascular disease history before the index date. Similarly, no statistically significant difference was found between the two drugs in the subgroup analysis. Febuxostat was not associated with a significantly increased risk of cardiovascular disease.

Effect of low dose allopurinol on glycemic control and glycemic variability in patients with type 2 diabetes mellitus: A cross-sectional study

BackgroundType 2 diabetes mellitus (DM), gout, and asymptomatic hyperuricemia are inter-connected pathologies. Glycemic control (GC), involving a range of treatments is central to the management of DM, whereas allopurinol continues to be the most widely recommended urate lowering agent. Allopurinol has been shown to possess anti-oxidant properties: this study explores the potential effect of allopurinol on glucose homeostasis. MethodsThis is an observational study with a cross-sectional design performed on patients with type 2 diabetes mellitus (DM), recruited from centers in Saudi Arabia. Patients were divided into two groups; allopurinol users; (for gout or asymptomatic hyperuricemia) and a matching disease control group. Patient demographics, co-morbid conditions, biochemical tests, and pharmacological treatments were extracted from electronic records to investigate the effect of allopurinol therapy on Glycemic control (GC), as assessed by glycated haemoglobin (HbA1c as primary endpoint), and on parameters of glycaemic variability (GV) (secondary endpoints). ResultsA total of 194 patients with type 2 DM were recruited (97 in both groups). The two groups were matched for age, sex, and duration of DM: mean age: 59.4 years, 73% males, and 122 months in the allopurinol group vs 59.6 years, 73% males, and 113 months in the control group. Antidiabetic medications were matched between the two groups. In the allopurinol group, it was prescribed with a daily dose of 100 mg, for 77% of the patients, with median duration of 39.5 months. HbA1c values were; 6.90% (6.20, 7.80) in the allopurinol group vs 7.30% (6.60, 8.40) in the control group (P = 0.010). Parameters of GV were calculated from 3 consecutive fasting blood sugar (FBS) readings: variability independent of the mean (VIM) was 0.140 in the allopurinol group vs 0.987 in the control group (P < 0.001). ConclusionConcomitant low-dose allopurinol therapy in patients with type 2 DM was associated with modest but significant improvements in GC and GV.

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77). In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. UK National Institute for Health and Care Research.

Effects of allopurinol on renal function in patients with diabetes: a systematic review and meta-analysis

Background/Objective Diabetes mellitus is a common “non-gout” disease with high incidence. Several studies have shown that serum uric acid level in patients with diabetes is higher than that in healthy individuals, and is accompanied by severe albuminuria and high serum creatinine (Scr). Recent clinical studies have found that uric acid-lowering therapy (such as allopurinol) could reduce urinary albumin excretion rates (UAER) and Scr, increase eGFR, and thus reduce kidney damage in patients with diabetes. Therefore, this meta-analysis [PROSPERO CRD42021274465] intended to evaluate the efficacy and safety of allopurinol in patients with diabetes mellitus. Methods We thoroughly searched five electronic resource databases for randomized controlled trials (RCTs) that compared the efficacy and safety of allopurinol versus conventional treatment or placebo for the treatment of patients with diabetes mellitus. Predetermined outcomes were considered continuous variables, mean difference (MD) was used for the determination of effect size (standardized mean difference [SMD] was used to determine the effect size when there were different evaluation criteria in different articles), and the corresponding 95% confidence interval (CI) was calculated. All outcome measures were analyzed using a random-effects model for data analysis. Results Ten eligible trials with a total of 866 participants were included in the meta-analysis. Allopurinol was more effective in decreasing serum uric acid (SUA) levels compared with conventional treatment (p = 0.0001) or placebo (p < 0.00001). Moreover, the levels of 24-hour urine protein were significantly lower in the allopurinol group (p < 0.00001). The subgroup analysis of Scr showed that the Scr of patients with an allopurinol treatment duration of fewer than six months was significantly lower than that of the control group (p = 0.03). No significant difference in adverse events (AEs) was identified between the treatment and control groups. Conclusions Our meta-analysis of RCTs showed that oral administration of allopurinol effectively reduced SUA levels in patients with diabetes, and patients’ renal function was protected. More RCTs with larger sample sizes and higher quality are needed to clarify the role of allopurinol use in decreasing blood pressure, maintaining blood glucose levels, and improving renal function in patients with diabetes.

Postinjury Treatment to Mitigate the Effects of Aeromedical Evacuation After Traumatic Brain Injury in a Porcine Model

IntroductionEarly aeromedical evacuation after traumatic brain injury (TBI) has been associated with worse neurologic outcomes in murine studies and military populations. The goal of this study was to determine if commonly utilized medications, including allopurinol, propranolol, or tranexamic acid (TXA), could mitigate the secondary traumatic brain injury experienced during the hypobaric and hypoxic environment of aeromedical evacuation. MethodsPorcine TBI was induced via controlled cortical injury. Twenty nonsurvival pigs were separated into four groups (n = 5 each): TBI+25 mL normal saline (NS), TBI+4 mg propranolol, TBI+100 mg allopurinol, and TBI+1g TXA. The pigs then underwent simulated AE to an altitude of 8000 ft for 4 h with an SpO2 of 82-85% and were sacrificed 4 h later. Hemodynamics, serum cytokines, and hippocampal p-tau accumulation were assessed. An additional survival cohort was partially completed with TBI/NS (n = 5), TBI/propranolol (n = 2) and TBI/allopurinol groups (n = 2) survived to postinjury day 7. ResultsThere were no significant differences in hemodynamics, tissue oxygenation, cerebral blood flow, or physiologic markers between treatment groups and saline controls. Transient differences in IL-1b and IL-6 were noted but did not persist. Neurological Severity Score (NSS) was significantly lower in the TBI + allopurinol group on POD one compared to NS and propranolol groups. P-tau accumulation was decreased in the nonsurvival animals treated with allopurinol and TXA compared to the TBI/NS group. ConclusionsAllopurinol, propranolol, and TXA, following TBI, do not induce adverse changes in systemic or cerebral hemodynamics during or after a simulated postinjury flight. While transient changes were noted in systemic cytokines and p-tau accumulation, further investigation will be needed to determine any persistent neurological effects of injury, flight, and pharmacologic treatment.