Allopurinol Treatment Research Articles

Clinical Case of Feline Leishmaniosis: Therapeutic Approach and Long-Term Follow-Up.

Simple SummaryIn the present report, clinical, diagnostic, and therapeutical findings observed in a case of feline leishmaniosis (FeL) along with its long-term follow-up data are reported with the aim to provide more evidence-based data on the treatment of this important zoonotic vector-borne disease of cats. The present study represents one of the few reports of FeL with a 28-month follow-up period. This case underlines the effectiveness of allopurinol and highlights how the interruption of treatment frequently leads to relapse, impairing the animal’s health condition and prognosis.The response to allopurinol treatment and survival time of a case of feline leishmaniosis in a FIV co-infected cat is herein reported. In May 2019, a 13-year-old neutered European Shorthair male was referred due to weight loss and exfoliative dermatitis. Lymphadenomegaly and splenomegaly were detected upon clinical inspection, while the presence of several Leishmania infantum amastigotes were detected on splenic and lymphonodal fine needle aspiration (FNA). Allopurinol (10 mg/kg PO q 12 h) was administered. After two months, the cat’s clinical symptoms disappeared, and the owners decided to interrupt the therapy. In February, two reddish nodular fleshy neoformations appeared in both eyes, and amastigotes of Leishmania were detected by cytology on conjunctival swabs. Allopurinol treatment was re-started at the same rate; the ocular lesions regressed in two weeks, and the owner again decided to interrupt the therapy. In July, the patient had a new relapse, but the owner, tired of continuous relapses, refused further treatment of the disease. The cat’s health condition continued to worsen: in October 2021, the ocular lesions appeared again, and in November the patient died. This case underlines the effectiveness of allopurinol and highlights how interruption of treatment frequently leads to relapse, impairing the animal’s health condition and prognosis.

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.

Therapeutic effects of allopurinol on the function of left ventricular and activity of matrix metalloproteinase enzymes (MMPs) in patients with chronic heart failure.

Heart failure is a growing public health problem, especially in the elderly, often occurring due to ischemia and coronary artery disease. Allopurinol can protect against myocardial ischemia and improve myocardial energy utilization during ischemia. On the other hand, matrix metalloproteinase (MMP) enzymes play an essential role in causing atherosclerosis, obstruction, and myocardial infarction. Therefore, in the present study, the effect of allopurinol on the function of the left ventricular and the activity of MMP-1, MMP-2, MMP-3, and MMP-9 were evaluated in heart failure patients. In this clinical trial, 82 patients were randomly assigned to allopurinol or placebo in addition to standard treatment. Echocardiographic evaluations were performed before treatment and six months after treatment. Also, after allopurinol treatment, plasma and peripheral blood mononuclear cells were extracted from control and intervention groups. The active form of MMPs was measured by ELISA and mRNA expression by Real-time PCR. The rate of change in left ventricular ejection fraction in the allopurinol group was significantly higher than patients in the control group. There was also found more improvement in NYHA class in patients receiving allopurinol than in the control group. ELISA results showed that all plasma MMP levels in the control group were significantly higher than those in the allopurinol group (P<0.001). Quantitative determination of mRNA expression in MMPs by Real-time RT-PCR revealed that, except for MMP-9, there was no significant difference in the expression of evaluated MMPs between the treatment and control groups. In general, the results showed that long-term administration of allopurinol improves left ventricular function, and it has beneficial effects on the life quality of patients with heart failure.

Antioxidation and Nrf2-mediated heme oxygenase-1 activation contribute to renal protective effects of hydralazine in diabetic nephropathy

Reactive oxygen species (ROS) and oxidative stress are associated with the progression of diabetic nephropathy (DN). Hydralazine is an antihypertensive agent and may act as a xanthine oxidase (XO) inhibitor to reduce uric acid levels in a mouse renal injury model. This study aimed to investigate the potential mechanisms of hydralazine in experimental DN. Streptozotocin-induced diabetic mice were fed a high-fat diet to generate DN. Human renal proximal tubular epithelial cells were used in vitro. Nitrendipine and allopurinol which can reduce blood pressure or XO activity levels, were used as two positive controls. Hydralazine downregulated NF-κB/p38 signaling pathways and reduced TNF-α/IL-6 expressions in high glucose-stimulated renal proximal tubular epithelial cells. Hydralazine reduced in vitro ROS production via XO inhibition and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated heme oxygenase (HO)-1 activation. Furthermore, hydralazine reduced high glucose-induced apoptosis by downregulating PARP/caspase-3 signaling. Hydralazine and allopurinol but not nitrendipine reduced serum uric acid levels and systemic inflammation. Hydralazine and allopurinol treatment improved renal function with decreased urinary albumin-to-creatinine ratios, glomerular hypertrophy, glomerulosclerosis, and fibrosis in the kidney of DN mice. While both hydralazine and allopurinol downregulated XO and NADPH oxidase expression, only hydralazine upregulated Nrf2/HO-1 renal expression, suggesting the additional effects of hydralazine independent of XO/ NADPH oxidase inhibition. In conclusion, hydralazine protected renal proximal tubular epithelial cells against the insults of high glucose and prevented renal damage via XO/NADPH oxidase inhibition and Nrf-2/HO-1 activation, suggesting the comprehensive antioxidation and anti-inflammation mechanisms for the management of DN.

Carvacrol Alleviates Hyperuricemia-Induced Oxidative Stress and Inflammation by Modulating the NLRP3/NF-κB Pathwayt.

PurposeGouty arthritis is generally induced by the accumulation of monosodium urate (MSU) crystals in the joints due to elevated serum uric acid levels, potentially leading to serious pathological disorders such as nephrolithiasis, renal failure, and acute gouty arthritis. In this study, we aimed to validate the anti-gout effects of carvacrol, a phenolic monoterpene.Materials and MethodsMale Sprague–Dawley rats were divided into normal saline, disease group by injecting potassium mono-oxonate (PO) at a dose of 250 mg/kg, and three treatment groups, either with carvacrol 20 mg/kg or 50 mg/kg and 10 mg/kg allopurinol. The blood and tissue samples were subsequently collected and analyzed using different biochemical and histopathological techniques.ResultsOur results revealed a significant increase in the serum levels of oxidative stress-related markers, namely, uric acid and C-reactive protein (CRP), and NLRP3 inflammasome-dependent inflammatory mediators, including nuclear factor kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α). Carvacrol administration for seven consecutive days exhibited significant anti-hyperuricemic and anti-inflammatory effects in a dose-dependent manner. Notably, the 50 mg/kg carvacrol treatment was observed to produce results similar to the allopurinol treatment. Furthermore, the renal safety of carvacrol was confirmed by the renal function test.ConclusionCarvacrol potentially alleviates hyperuricemia-induced oxidative stress and inflammation by regulating the ROS/NRLP3/NF-κB pathway, thereby exerting protective effects against joint degeneration.

A meta-analysis of allopurinol therapy and the risk of prostate cancer.

Abstract Objective: The aim of the study was to investigate the risk of prostate cancer among people with gout and/or hyperuricemia who used allopurinol and who did not use allopurinol. Methods: We conducted a meta-analysis to identify the cohort and case-control studies by searching PubMed and Web of Science. We used the random-effects model to calculate the pooled risk ratio with 95% confidence interval for the risk of prostate cancer associated with allopurinol treatment. Results: There were 5 cohort studies and 2 case-control studies included in the meta-analysis. All 7 eligible studies were published between 2012 and 2021. The study period ranged from 8 to 13years. The number of study subjects ranged from 25,770 to 1,623,550. The age of study subjects ranged from 20 to 99years. Overall, allopurinol treatment was not associated with the risk of prostate cancer (risk ratio = 1.13, 95% confidence interval = 0.96-1.34 and P = .13). The heterogeneity was high between studies (I2 = 93%). Conclusions: Our meta-analysis reveals that no association can be found between allopurinol treatment and the risk of prostate cancer among people with gout and/or hyperuricemia. We propose that the inhibition of xanthine oxidase and the reduction of serum uric acid via allopurinol treatment do not affect the probability of developing prostate cancer. Further studies are needed to confirm our findings. Key Points

Effect of allopurinol drug use on GFR and proteinuria in patients with renal transplant recipients (ADOPTR study)

BackgroundHyperuricemia has been associated with the development of hypertension, cardiovascular, and renal disease. However, there is no data about the effect of lowering uric acid level on renal functions and proteinuria in renal transplant recipients. This study aimed to investigate the effect of allopurinol treatment on renal functions in renal transplant recipients (RTR). MethodsA total of 245 patients with renal transplantation were included in this randomized, placebo-controlled study. Patients were randomized to receive either placebo (121 patients) or 300 mg/day allopurinol (124 patients). We have examined uric acid, urinary protein creatinin ratio, MDRD (the modification of diet in renal diseases) and CRP (C-reactive protein) before and 24 weeks after treatment in both group. ResultsIn the allopurinol group, the mean serum uric acid levels, eGFR (estimated glomerular filtration rate), and creatinine urinary albumin creatinin ratio (UACR) significantly improved (p < 0.001). Also uric acid level was positively correlated with the UACR (r = 0,645 p < 0.001) and negatively correlated with MDRD (r = −0,387 p < 0.05) in allopurinol treatment group. A statistically significant increase in CRP level was observed (p < 0,05) in plasebo group. Multivariate regression analysis showed that uric acid was positively correlated with UACR (r = 0,473, β = 0.021, p = 0.002) and negatively correlated with MDRD (r = −0554 β = 0.016, P = 0.001) in allopurinol treatment RTR. ConclusionUrate, a salt of uric acid, is lowered by allopurinol treatment resulting in improved eGFR and decreased proteinuria, when compared to the placebo group. Therefore, we suggest that allopurinol therapy should be part of the management of kidney transplant patients with normal kidney function. Long-term follow-up studies will be useful in revealing the effect of uric acid management on kidney functions and proteinuria.

The Prospective Effect of Allopurinol on the Oxidative Stress Index and Endothelial Dysfunction in Covid-19.

SARS-CoV-2 by the direct cytopathic effect or indirectly through the propagation of pro-inflammatory cytokines could cause endothelial dysfunction (ED) and oxidative stress (OS). It has been reported that OS is triggered by various types of viral infections, including SARS-CoV-2. Into the bargain, allopurinol is regarded as a potent antioxidant that acts through inhibition of xanthine oxidase (XO), which is an essential enzyme of purine metabolism. Herein, the present study aimed to find the potential protective effects of allopurinol on the biomarkers of OS and ED in patients with severe Covid-19. This single-center cohort study recruited 39 patients with mild-moderate Covid-19 compared with 41 patients with severe Covid-19. Nineteen patients with severe Covid-19 were on the allopurinol treatment because of underlying chronic gout 3 years ago compared with 22 Covid-19 patients not on this treatment. The recruited patients were allocated into three groups: group I, mild-moderate Covid-19 on the standard therapy (n = 39); group II, severe Covid-19 patients on the standard therapy only (n = 22); and group III, severe Covid-19 patients on the standard therapy plus allopurinol (n = 19). The duration of the study was 3 weeks from the time of hospitalization till the time of recovery. In addition, inflammatory biomarkers (D-dimer, LDH, ferritin, CRP, procalcitonin), neutrophil–lymphocyte ratio (NLR), endothelin-1 (ET-1), uric acid and oxidative stress index (OSI), CT scan score, and clinical score were evaluated at the time of admission and discharge regarding the effect of allopurinol treatment adds to the standard treatment of Covid-19. Allopurinol plus standard treatment reduced LDH, ferritin, CRP, procalcitonin, and ET-1 serum level significantly (P < 0.05) compared with Covid-19 patients on standard treatment. Besides, neutrophil (%), lymphocyte (%), and neutrophil–lymphocyte ratio (NLR) were reduced in patients with severe Covid-19 on standard treatment plus allopurinol compared with Covid-19 patients on standard treatment alone (P < 0.01). OSI was higher in patients with severe Covid-19 than mild-moderate Covid-19 patients (P = 0.00001) at admission. At the time of discharge, the oxidative status of Covid-19 patients was significantly improved compared with that at admission (P = 0.01). In conclusion, Covid-19 severity is linked with high OS and inflammatory reaction with ED development. High uric acid in patients with severe Covid-19 is correlated with high OS and inflammatory biomarkers. Allopurinol with standard treatment in patients with severe Covid-19 reduced oxidative and inflammatory disorders with significant amelioration of ED and clinical outcomes.

Xanthinuria secondary to allopurinol treatment in dogs with leishmaniosis: Current perspectives of the Iberian veterinary community

Xanthinuria is a significant adverse effect in dogs on long-term allopurinol for treatment of leishmaniosis. The study aims to investigate how the Iberian veterinary community (IVC) identifies, manages, and proactively prevents xanthinuria secondary to allopurinol treatment. A cross-sectional study was conducted using an online survey, translated into two languages, and disseminated to the IVC via social networking forums. Respondents were asked to share their treatment regimens, adverse effects attributed to treatment, as well as preventive and reactive measures against xanthuria. Of two-hundred and thirty respondents, 99.6% prescribe allopurinol for canine leishmaniosis. Xanthinuria was estimated to happen in less than one out of every four dogs by 91.7% of the clinicians. Xanthinuria has been detected by 71.6% of respondents at least once. Three out of every four respondents inform owners about deleterious effects of allopurinol, and 28.4% consider implementing a change in diet in advance of treatment as a proactive measure. To monitor xanthinuria, urinalysis and diagnostic imaging are used by 71.2% and 31% of clinicians respectively. When xanthinuria is detected, 43.2% of the respondents discontinue allopurinol, 24% replace it by nucleotide-analogs, 14.9% reduce its dosage, and 3.1% split its dosage but increase administration frequency. Additional measures are taken by 72.1% of the respondents, 59.4% of whom prescribe a low-purine diet. The IVC recognizes xanthinuria as a fairly common secondary effect of long-term allopurinol treatment in dogs with leishmaniosis and recommends periodically monitoring and preventive measures.

Cardiovascular risk associated with allopurinol or benzbromarone treatment in patients with gout.

Background:In previous studies, cardiovascular (CV) risk was increased in patients with gout. The effects of uric acid–lowering therapy on CV risk in gout patients have been investigated in numerous studies; however, allopurinol and benzbromarone have rarely been compared.Objectives:To compare CV risk based on allopurinol and benzbromarone treatment in Korean gout patients.Design:A nationwide population-based retrospective cohort study.Methods:We used South Korea database of the Health Insurance Review and Assessment (HIRA) service to identify gout patients ⩾18 years of age who newly started allopurinol or benzbromarone between 2009 and 2015. The primary outcome of the study was the occurrence of a composite CV endpoint, which included coronary revascularization, hospitalization due to myocardial infarction, ischemic stroke, and transient ischemic attack. Cox proportional hazard regression analysis and Kaplan–Meier curves were used for analysis.Results:The study included 257,097 allopurinol initiators and 7868 benzbromarone initiators. Compared with allopurinol initiators, the adjusted hazard ratio (aHR) of the composite CV endpoint of benzbromarone initiators was 1.01 [95% confidence interval (CI): 0.83−1.21], which was not significantly different. The results did not change even when 1:3 propensity score matching was performed for baseline characteristics. In subgroup analysis of high-risk patients with CV disease, significant difference was not observed between allopurinol and benzbromarone initiators.Conclusion:In this study, significant difference was not found in CV risk between allopurinol and benzbromarone initiators. In the high-CV-risk group, the incidence of CV events did not differ between allopurinol and benzbromarone initiators.

Allopurinol to reduce cardiovascular morbidity and mortality: A systematic review and meta-analysis.

To compare the effectiveness of allopurinol with no treatment or placebo for the prevention of cardiovascular events in hyperuricemic patients. Pubmed, Web of Science and Cochrane library were searched from inception until July 2020. Randomized controlled trials (RCT) and observational studies in hyperuricemic patients without significant renal disease and treated with allopurinol, versus placebo or no treatment were included. Outcome measures were cardiovascular mortality, myocardial infarction, stroke, or a combined endpoint (CM/MI/S). For RCT's a random effects meta-analysis was performed. For observational studies a narrative synthesis was performed. Of the original 1995 references we ultimately included 26 RCT's and 21 observational studies. We found a significantly reduced risk of combined endpoint (Risk Ratio 0.65 [95% CI] [0.46 to 0.91]; p = 0.012) and myocardial infarction (RR 0.47 [0.27 to 0.80]; p = 0.01) in the allopurinol group compared to controls. We found no significant effect of allopurinol on stroke or cardiovascular mortality. Of the 15 observational studies with sufficient quality, allopurinol was associated with reduced cardiovascular mortality in 1 out of 3 studies that reported this outcome, myocardial infarction in 6 out of 8, stroke in 4 out of 7, and combined end-point in 2 out of 2. Cardiovascular benefit was only observed when allopurinol therapy was prolonged for more than 6 months and when an appropriate allopurinol dose was administered (300 mg or more/day) or sufficient reduction of serum urate concentration was achieved (<0.36 mmol/l). Data from RCT's and observational studies indicate that allopurinol treatment reduces cardiovascular risk in patients with hyperuricemia. However, the quality of evidence from RCTs is low to moderate. To establish whether allopurinol lowers the risk of cardiovascular events a well-designed and adequately powered randomized, placebo-controlled trial is needed in high-risk patients with hyperuricemia. PROSPERO registration CRD42018089744.

Association between the use of allopurinol and risk of increased thyroid-stimulating hormone level

Allopurinol is the first-line agent for patients with gout, including those with moderate‐to‐severe chronic kidney disease. However, increased thyroid-stimulating hormone (TSH) levels are observed in patients with long-term allopurinol treatment. This large-scale, nested case–control, retrospective observational study analysed the association between allopurinol use and increased TSH levels. A common data model based on an electronic medical record database of 19,200,973 patients from seven hospitals between January 1997 and September 2020 was used. Individuals aged > 19 years in South Korea with at least one record of a blood TSH test were included. Data of 59,307 cases with TSH levels > 4.5 mIU/L and 236,508 controls matched for sex, age (± 5), and cohort registration date (± 30 days) were analysed. An association between the risk of increased TSH and allopurinol use in participants from five hospitals was observed. A meta-analysis (I2 = 0) showed that the OR was 1.51 (95% confidence interval: 1.32–1.72) in both the fixed and random effects models. The allopurinol intake group demonstrated that increased TSH did not significantly affect free thyroxine and thyroxine levels. After the index date, some diseases were likely to occur in patients with subclinical hypothyroidism and hypothyroidism. Allopurinol administration may induce subclinical hypothyroidism.

Meta-analysis assessing cardiovascular outcomes with febuxostat versus allopurinol for patients with gout

Abstract Background Gout, the most common inflammatory arthritis in the USA, represents an established risk factor for cardiovascular disease and coronary artery disease mortality. In addition, patients with gout experience an increased risk for non-fatal myocardial infarction, while they might also feature increased risk for stroke. Recent real-world data also highlight the association between gout and atrial fibrillation, which inevitably augments cardiovascular burden. Allopurinol, a xanthine oxidase inhibitor, remains the uric acid-lowering treatment option of first choice, while febuxostat is prescribed, when allopurinol is contraindicated or not tolerated. Unfortunately, medication adherence among gout patients is poor, associated with age and related co-morbidities. Purpose We sought to determine the comparative efficacy of febuxostat versus allopurinol across surrogate cardiovascular outcomes of interest, by pooling data from the 2 dedicated cardiovascular outcome trials available so far. The motive for this analysis was the U.S. Food and Drug Administration (FDA) warning raised after the publication of the CARES trial, regarding the increased risk for cardiovascular and all-cause death with febuxostat compared to allopurinol. Methods We pooled data from the 2 dedicated cardiovascular outcome trials (CARES and FAST) and we assessed the following cardiovascular outcomes of interest: cardiovascular death, all-cause death, non-fatal myocardial infarction (MI), non-fatal stroke, fatal MI, fatal stroke, transient ischemic attack, hospitalization for heart failure, coronary revascularization, cerebrovascular revascularization and atrial fibrillation. Risk of bias was low across the included studies. Results Our analysis in a total of 12,318 patients with gout showed that febuxostat compared to allopurinol treatment does not confer significant risk reduction for any of the assessed, prespecified surrogate outcomes in a study population with significant cardiovascular co-morbidities (Figure 1). One third of patients enrolled in the FAST trial and 40% of the patients enrolled in the CARES trial had pre-existing cardiovascular disease, as depicted in Figure 2. Heterogeneity was low for the vast majority of the assessed outcomes, except for cardiovascular and all-cause death and fatal MI. Conclusions There is no significant difference across surrogate cardiovascular outcomes of interest between febuxostat and allopurinol in patients with gout and cardiovascular co-morbidities. Febuxostat seems to be a safe treatment alternative to allopurinol, despite initial concerns in terms of its cardiovascular safety. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Acute Tumor Lysis Syndrome: A Metabolic Emergency in Cancer Patients

Tumor lysis syndrome (TLS) can be a life-threatening complication that occurs following the onset of chemotherapy treatment, most commonly in association with high-grade lymphoproliferative pathologies such as acute lymphoblastic leukemia and Burkitt lymphoma. The massive cell lysis caused by cytotoxic therapy leads to the rapid release in the blood of intracelullary products and the onset of severe metabolic and electrolytic complications (hyperkalemia, hyperphosphatemia, hypocalcemia and hyperuricemia) upto the acute renal failure. This article describes the incidence and pathophysiological basis of TLS, focusing on the new therapeutic strategies implemented over the last few years, especially with regard to the treatment of hyperuricemia. In particular, it highlights the characteristics of a recent drug, Rasburicase, as a safe and effective alternative, compared to traditional allopurinol therapy, for prophylaxis and treatment of children with hyperuricemia induced by chemotherapy.

Assessing the Causal Relationships Between Insulin Resistance and Hyperuricemia and Gout Using Bidirectional Mendelian Randomization.

Hyperuricemia is closely associated with insulin resistance syndrome (and its many cardiometabolic sequelae); however, whether they are causally related has long been debated. We undertook this study to investigate the potential causal nature and direction between insulin resistance and hyperuricemia, along with gout, by using bidirectional Mendelian randomization (MR) analyses. We used genome-wide association data (n = 288,649 for serum urate [SU] concentration; n = 763,813 for gout risk; n = 153,525 for fasting insulin) to select genetic instruments for 2-sample MR analyses, using multiple MR methods to address potential pleiotropic associations. We then used individual-level, electronic medical record-linked data from the UK Biobank (n = 360,453 persons of European ancestry) to replicate our analyses via single-sample MR analysis. Genetically determined SU levels, whether inferred from a polygenic score or strong individual loci, were not associated with fasting insulin concentrations. In contrast, genetically determined fasting insulin concentrations were positively associated with SU levels (0.37 mg/dl per log-unit increase in fasting insulin [95% confidence interval (95% CI) 0.15, 0.58]; P = 0.001). This persisted in outlier-corrected (β = 0.56 mg/dl [95% CI 0.45, 0.67]) and multivariable MR analyses adjusted for BMI (β = 0.69 mg/dl [95% CI 0.53, 0.85]) (P < 0.001 for both). Polygenic scores for fasting insulin were also positively associated with SU level among individuals in the UK Biobank (P < 0.001). Findings for gout risk were bidirectionally consistent with those for SU level. These findings provide evidence to clarify core questions about the close association between hyperuricemia and insulin resistance syndrome: hyperinsulinemia leads to hyperuricemia but not the other way around. Reducing insulin resistance could lower the SU level and gout risk, whereas lowering the SU level (e.g., allopurinol treatment) is unlikely to mitigate insulin resistance and its cardiometabolic sequelae.

Biomarkers of iron status in allopurinol-treated renal stone patients

Limited evidence exists on the effect of xanthine oxidase inhibitors in nephrolithiasis patients on iron status markers, beyond their effects on urate. The aim of this study was to investigate whether allopurinol therapy was associated with a significant impact on parameters related to iron status, in patients with renal stones. Allopurinol treatment was associated with a nonsignificant decline in serum uric acid. There were no significant differences in serum levels of transferrin and ferritin after treatment with allopurinol compared to pre-treatment levels. A non-significant fall in serum levels of haptoglobin was registered. The drug was associated with a significant rise in serum iron levels. Serum uric acid and iron did not show a significant correlation with any parameter in the study. Allopurinol exerted an overall non-significant effect on iron metabolism in nephrolithiasis patients, save for serum iron, this entails lack of untoward effects in populations with-iron related conditions.

Cardiac Affection in Pediatric CKD Patients in Relation to Hyperuricemia and its Treatment

Abstract Background: The prevalence of hyperuricemia in CKD pediatric patients increases in parallel with the estimated glomerular filtration rate (eGFR) decline, which is present in 40% to 60% of patients with CKD stages 1 to 3 and in 70% of patients with CKD stage 4, in this study, we aimed to study the prevalence of hyperuricemia among CKD paediatric patients in stages 2,3,4 and its effect on cardiac indices, and effect of allopurinol treatment on cardiac indices. Aim of Study: The Prevalence of hyperuricemia among CKD paediatric patients and its effect on cardiac indices. The impact of treatment with allopurinol for 6 months in hyperu-ricemic CKD pediatric patients on cardiac indices. Patients and Methods: A prospective cohort study was conducted on 78 CKD pediatric patients in stages 2,3,4, recruited from nephrology clinic Ain Shams University Hos-pital during the period from December 2019 to February 2020. Results: There were highly statistically significant negative correlation between serum uric acid level and GFR with p-value >0.001 and there were a highly significant relation between the level of uric acid and CKD stage with p-value >0.001, and there were a highly significant diffirane in cardiac indices before and after the treatment. There was a highly significant relationship between the level of uric acid before and after allopurinol treatment which showing the effectiveness of the drug for decreasing the uric acid level in the blood and it’s effect on the kidney and cardiovascular systeme. Conclusion: 6 months administration of allopurinol treat-ment in hyperuriamic CKD pediatric patients in stages 2,3,4 resulted in improving the laboratory data of (uric acid level, serum creatinine, GFR) and showing a significant effect on cardiac indices (LV structure, systolic and diastolic function).

A CASE REPORT ON ALLOPURINOL INDUCED DRESS SYNDROME

Allopurinol-induced DRESS Syndrome or Drug Rash with Eosinophilia and Systemic Symptom is a rare but potentially fatal drug reaction. Fever, rashes, swelling, and hematologic abnormalities, particularly short-term or long-term injury to one or more organs, have been reported by over 0.4 percent of patients following the course of medicine. Here, a 54-year-old female patient was admitted to the hospital with complaints of fever, purpuric rashes over the body with itching mainly in the oral cavity and lips, and the extent to the upper back and lower limbs for three days. She had known complaints of Type 2 Diabetes, Systemic hypertension, Coronary artery disease with recent NSTEMI, Dyslipidaemia, Psychosis (20y), and Chronic kidney disease. She had been taking Allopurinol for the past three months for hyperuricemia. Allopurinol treatment stopped while topical Steroid treatment started along with supportive therapy. After ten days, the rashes improved significantly, allowing her to leave the hospital.

Effectiveness of Allopurinol in Reducing Mortality: Time-Related Biases in Observational Studies.

The treatment of gout with allopurinol is effective at reducing urate levels and the frequency of flares. Several observational studies have shown important reductions in mortality with allopurinol use, with wide variations in results. We undertook this review to assess the extent of bias in these studies, particularly time-related biases such as immortal time bias. We searched the literature to identify all observational studies describing the effect of allopurinol use versus nonuse on all-cause mortality. We identified 12 observational studies, of which 3 were affected by immortal time bias and 3 by immeasurable time bias, while the remaining 6 studies avoided these time-related biases. Reductions in all-cause mortality with allopurinol use were observed among the studies with immortal time bias, with a pooled hazard ratio (HR) of death associated with allopurinol of 0.71 (95% confidence interval [95% CI] 0.50-1.01), as well as in those with immeasurable time bias (pooled HR 0.62 [95% CI 0.56-0.67]). The 6 studies that avoided these biases demonstrated a null effect of allopurinol on mortality (pooled HR 0.99 [95% CI 0.87-1.11]), though the lack of an analysis based on treatment adherence may have attenuated the effect. Observational studies are important to provide real-world data on medication effects. The observational studies showing significantly decreased mortality with allopurinol treatment cannot be used as evidence, however, mainly due to time-related biases that tend to greatly exaggerate the potential benefit of treatments. The ALL-HEART randomized trial, which is currently underway and evaluates the effect of adding allopurinol to usual care (compared to no added treatment), will provide reliable evidence on mortality.

Comparing the Effects of Febuxostat and Allopurinol in an Animal Model of Metabolic Syndrome

Introduction: Recent studies highlighted the association of hyperuricemia and metabolic syndrome (MS). The aim of this study was to compare the beneficial effects of febuxostat versus allopurinol on the biochemical changes that occur in MS. Methods: Forty adult male Sprague Dawley albino rats were used in the study. Insulin resistance and MS were induced by administration of a high-fructose diet for 8 weeks. Follow-up of changes in weight, blood pressure, serum biochemical parameters, serum antioxidant catalase, and glutathione peroxidase activities was done. At the end of the study, animals were sacrificed, and the thoracic aorta was isolated for in vitro study of the endothelial integrity. Results: Allopurinol and febuxostat treatment induced significant reduction in body weight, systolic blood pressure, blood glucose, insulin, lipids, and improved kidney functions and endothelial integrity compared to nontreated rats. Febuxostat was more effective than allopurinol in normalizing serum fasting glucose, uric acid, catalase, and glutathione peroxidase activities. Conclusion: Xanthine oxidase inhibitors ameliorated the effects of MS. Febuxostat was mildly superior to allopurinol in lowering serum fasting glucose, lipids, uric acid, and antioxidant enzyme activities.