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Saudi Journal of Kidney Diseases and... Jul 2023Hyperuricemia is a risk factor for the progression of chronic kidney disease (CKD). We compared febuxostat versus allopurinol in the progression of CKD and hyperuricemia...
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.
Topics: Humans; Febuxostat; Allopurinol; Hyperuricemia; Glomerular Filtration Rate; Gout Suppressants; Uric Acid; Renal Insufficiency, Chronic; Treatment Outcome
PubMed: 38345582
DOI: 10.4103/1319-2442.395443 -
International Journal of Molecular... Jan 2024Vascularized composite allotransplantation (VCA) represents a promising reconstructive solution primarily conducted to improve quality of life. However, tissue damage...
Vascularized composite allotransplantation (VCA) represents a promising reconstructive solution primarily conducted to improve quality of life. However, tissue damage caused by cold-ischemia (CI) storage prior to transplant represents a major factor limiting widespread application. This study investigates the addition of the novel free radical scavenger PrC-210 to UW Organ Preservation Solution (UW Solution) to suppress CI-induced skeletal muscle injury in a rat hind limb amputation model. Lewis rats received systemic perfusion of UW solution +/- PrC-210 (0 mM control, 10 mM, 20 mM, 30 mM, or 40 mM), followed by bilateral transfemoral amputation. Limbs were stored in 40 mL of the same perfusate at 4 °C for 48 h. Muscle punch biopsies were taken at set times over the 48 h cold-storage period and analyzed for caspase-3,7 activity, cytochrome C levels, and qualitative histology. A single 15 s perfusion of PrC-210-containing UW Solution conferred a dose-dependent reduction in CI-induced muscle cell death over 48 h. In the presence of PrC-210, muscle cell mitochondrial cytochrome C release was equivalent to 0 h controls, with profound reductions in the caspase-3,7 apoptotic marker that correlated with limb histology. PrC-210 conferred complete prevention of ROS-induced mitochondrial lysis in vitro, as measured by cytochrome C release. We conclude that the addition of 30 mM PrC210 to UW Solution conferred the most consistent reduction in CI limb damage, and it warrants further investigation for clinical application in the VCA setting.
Topics: Rats; Animals; Free Radical Scavengers; Caspase 3; Composite Tissue Allografts; Cytochromes c; Quality of Life; Rats, Inbred Lew; Glutathione; Allopurinol; Insulin; Ischemia; Organ Preservation; Cold Temperature; Reperfusion Injury; Diamines; Sulfhydryl Compounds; Raffinose; Organ Preservation Solutions; Adenosine
PubMed: 38338887
DOI: 10.3390/ijms25031609 -
Cureus Jan 2024Stevens-Johnson syndrome (SJS) is a severe and potentially debilitating skin reaction frequently related to medication use. Allopurinol and angiotensin-converting enzyme... (Review)
Review
Stevens-Johnson syndrome (SJS) is a severe and potentially debilitating skin reaction frequently related to medication use. Allopurinol and angiotensin-converting enzyme (ACE) inhibitors are commonly prescribed medications for prevalent health conditions worldwide, and their interaction associated with SJS warrants further investigation. A comprehensive literature search was performed to investigate cases as studies related to SJS occurring in patients with concomitant use of allopurinol and ACE inhibitors. We identified case reports and studies detailing hypersensitivity reactions, including SJS, attributed to a combination of allopurinol and ACE inhibitors. Despite the drug-drug interactions or lack thereof seen in patient populations, there is no definitive evidence of a pharmacokinetic interaction between allopurinol and ACE inhibitors. We were only able to find one case report specifically detailing SJS in a patient on combined ACE inhibitors and allopurinol. While the exact mechanism of the interaction is unclear, those reported cases of severe hypersensitivity reactions suggest a previous history of impaired renal function as a predisposing factor in the development of SJS. The potential risk of SJS with coadministration of ACE inhibitors and allopurinol is a drug-drug interaction that physicians should be aware of. This topic requires additional attention to determine if this drug combination should be avoided entirely in certain patients.
PubMed: 38333456
DOI: 10.7759/cureus.51899 -
Cancer Pathogenesis and Therapy Oct 2023Tumor lysis syndrome (TLS) remains a debilitating cause of hospitalization and death in patients with cancer and is a significant challenge for healthcare providers... (Review)
Review
Tumor lysis syndrome (TLS) remains a debilitating cause of hospitalization and death in patients with cancer and is a significant challenge for healthcare providers despite advancements in its management. This umbrella review analyzed the results of meta-analyses on the use of rasburicase in the treatment of patients with cancer. A literature search was performed of five databases (PubMed, Google Scholar, Cochrane Library, Scopus, Global Index Medicus, and ScienceDirect) for articles with full texts available online. A measurement tool to assess systematic reviews 2 (AMSTAR 2) was used to assess the quality of the included studies, and Review Manager software was used to conduct all statistical analyses. The systematic search identified eight relevant meta-analyses, with primary analyses including outcome data that analyzed mortality, renal failure, and comparisons with allopurinol. The pooled data showed that rasburicase effectively reduced TLS development and serum uric acid levels in children and adults with malignancies. Most outcomes did not differ significantly compared with those of allopurinol. Future trials should focus on the cost-effectiveness of rasburicase compared to that of allopurinol while including high-, intermediate-, and low-risk patients. Rasburicase is safe and effective for managing patients with TLS. However, recent large-scale meta-analyses have reported conflicting results. Most meta-analyses were graded as low to critically low as per AMSTAR 2. The analysis revealed that the benefit of rasburicase did not differ significantly from that of allopurinol, which has higher cost-effectiveness and fewer side effects.
PubMed: 38327601
DOI: 10.1016/j.cpt.2023.07.001 -
Canadian Urological Association Journal... May 2024Allopurinol is a commonly prescribed agent in the urologic population for the prevention of urinary stones. Although generally well-tolerated, several serious potential... (Review)
Review
Allopurinol is a commonly prescribed agent in the urologic population for the prevention of urinary stones. Although generally well-tolerated, several serious potential side effects can occur with its use. Allopurinol hypersensitivity syndrome (AHS), in particular, is a relatively rare but potentially life-threatening complication. With the observed increase in urinary stone disease, especially those of uric acid composition, it is likely that the use of allopurinol will increase. Urologists play an important role in the assessment and medical management of patients with urinary stones, thus a greater awareness of the potential adverse events associated with allopurinol use, especially AHS, is important, as well as strategies that can minimize such risks. Herein, we review the potential adverse effects of allopurinol. In addition, the results of a comprehensive review of the current literature on AHS will be presented, highlighting those patients at highest risk, reviewing the genetic susceptibility testing currently available, and providing guidance on best practices when allopurinol therapy is being considered.
PubMed: 38319608
DOI: 10.5489/cuaj.8685 -
BMC Pediatrics Jan 2024The purpose of our study is to investigate the laboratory and clinical features of tumor lysis syndrome (TLS) and acute kidney injury (AKI) in childhood non-Hodgkin...
OBJECTIVE
The purpose of our study is to investigate the laboratory and clinical features of tumor lysis syndrome (TLS) and acute kidney injury (AKI) in childhood non-Hodgkin lymphomas (NHL) and to reveal their impact on long term kidney function in survivors.
METHODS
Our single-center retrospective study included 107 patients (0-18 years old) with NHL who were admitted and treated at our hospital between 1998 and 2020. The relationship between TLS and age, gender, histopathological subgroup, tumor stage, lactate dehydrogenase (LDH) level at presentation, bone marrow and kidney involvement were assessed. The long-term renal functions of the patients were investigated.
RESULTS
80.3% of the patients were male with a median age of 9.8 years. The most common detected histopathological subgroup was Burkitt lymphoma. Hyperhydration with or without alkalinisation, and allopurinol were used in first-line treatment and prophylaxis of TLS. Laboratory TLS and clinical TLS was observed in 30.8% and 12.1% of patients, respectively. A significant correlation was found between young age, advanced stage, high LDH level at presentation, and TLS. AKI was observed in 12.1% of the patients. When the glomerular filtration rate values of the patients at the first and last admissions were compared after an average of 6.9 years, a mean decrease of 10 mL/min/1.73 m2 was found. It was not, however, found to be statistically significant.
CONCLUSION
Lower age, advanced stage, and high LDH level at presentation were found to be risk factors for TLS in our study. Long-term renal function loss was not observed in the survivors who received early and careful prophylaxis/treatment for TLS. The survivors are still being followed up.
Topics: Child; Humans; Male; Infant, Newborn; Infant; Child, Preschool; Adolescent; Female; Tumor Lysis Syndrome; Retrospective Studies; Lymphoma, Non-Hodgkin; Acute Kidney Injury; Survivors; Kidney
PubMed: 38297237
DOI: 10.1186/s12887-024-04549-w -
Trials Jan 2024Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or... (Randomized Controlled Trial)
Randomized Controlled Trial
Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).
BACKGROUND
Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol - a xanthine oxidase inhibitor - reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE.
METHODS/DESIGN
The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years.
RESULTS
The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and ."will be stratified for the two treatment groups.
DISCUSSION
The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03162653. Registered on 22 May 2017.
Topics: Child; Infant; Infant, Newborn; Humans; Hypoxia-Ischemia, Brain; Allopurinol; Control Groups; Brain Injuries; Hypothermia, Induced
PubMed: 38267942
DOI: 10.1186/s13063-023-07828-6 -
Saudi Pharmaceutical Journal : SPJ :... Feb 2024In this work, we investigated extract and an isolated compound for their potential as xanthine oxidase (XO) inhibitors, a target enzyme involved in inflammatory...
In this work, we investigated extract and an isolated compound for their potential as xanthine oxidase (XO) inhibitors, a target enzyme involved in inflammatory disorders. The prepared extract was subjected to column chromatography, and dinaphthodiospyrol S was isolated. Then XO inhibitory properties were assessed using a spectrophotometry microplate reader. DMSO was taken as a negative control, and allopurinol was used as a standard drug. The molecular docking study of the isolated compound to the XO active site was performed, followed by visualization and protein-ligand interaction. The defatted chloroform extract showed the highest inhibitory effect, followed by the chloroform extract and the isolated compound. The isolated compound exhibited significant inhibitory activity against XO with an IC value of 1.09 µM. Molecular docking studies showed that the compound strongly interacts with XO, forming hydrogen bond interactions with Arg149 and Cys113 and H-pi interactions with Cys116 and Leu147. The binding score of -7.678 kcal/mol further supported the potential of the isolated compound as an XO inhibitor. The quantum chemical procedures were used to study the electronic behavior of dinaphthodiospyrol S isolated from D. . Frontier molecular orbital (FMO) analysis was performed to understand the distribution of electronic density, highest occupied molecular orbital HOMO, lowest unoccupied molecular orbital LUMO, and energy gaps. The values of HOMO, LUMO, and energy gap were found to be -6.39, -3.51 and 2.88 eV respectively. The FMO results indicated the intramolecular charge transfer. Moreover, reactivity descriptors were also determined to confirm the stability of the compound. The molecular electrostatic potential (MEP) investigation was done to analyze the electrophilic and nucleophilic sites within a molecule. The oxygen atoms in the compound exhibited negative potential, indicating that they are favorable sites for electrophilic attacks. The results indicate its potential as a therapeutic agent for related disorders. Further studies are needed to investigate this compound's in vivo efficacy and safety as a potential drug candidate.
PubMed: 38261938
DOI: 10.1016/j.jsps.2023.101936 -
Research Square Jan 2024Effective xanthine oxidoreductase inhibition (XOI) urate-lowering treatment (ULT) to target significantly reduces gout flare burden and synovitis between 1-2 years...
BACKGROUND
Effective xanthine oxidoreductase inhibition (XOI) urate-lowering treatment (ULT) to target significantly reduces gout flare burden and synovitis between 1-2 years therapy, without clearing all monosodium urate crystal deposits. Paradoxically, treat to target ULT is associated with increased flare activity for at least 1 year in duration on average, before gout flare burden decreases. Since XOI has anti-inflammatory effects, we tested for biomarkers of sustained, effective ULT that alters gouty inflammation.
METHODS
We characterized the proteome of febuxostat-treated murine bone marrow macrophages. Blood samples (baseline and 48 weeks ULT) were analyzed by unbiased proteomics in febuxostat and allopurinol ULT responders from two, independent, racially and ethnically distinct comparative effectiveness trial cohorts (n=19, n=30). STRING-db and multivariate analyses supplemented determinations of significantly altered proteins via Wilcoxon matched pairs signed rank testing.
RESULTS
The proteome of cultured IL-1b-stimulated macrophages revealed febuxostat-induced anti-inflammatory changes, including for classical and alternative pathway complement activation pathways. At 48 weeks ULT, with altered purine metabolism confirmed by serum metabolomics, serum urate dropped >30%, to normal (<6.8 mg/dL) in all the studied patients. Overall, flares declined from baseline. Treated gout patient sera and peripheral blood mononuclear cells (PBMCs) showed significantly altered proteins (p<0.05) in clustering and proteome networks. CRP was not a useful therapy response biomarker. By comparison, significant serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains essential for C5b-9 membrane attack complex assembly and function; increase in the NLRP3 inflammasome activation promoter vimentin; increased urate crystal phagocytosis inhibitor sCD44; increased gouty inflammation pro-resolving mediator TGFB1; decreased phagocyte-recruiting chemokine PPBP/CXCL7, and increased monocyte/macrophage-expressed keratin-related proteins (KRT9,14,16) further validated by PBMC proteomics. STRING-db analyses of significantly altered serum proteins from both cohorts revealed a tight interactome network including central mediators of gouty inflammation (eg, IL-1B, CXCL8, IL6, C5).
CONCLUSIONS
Rewiring of inflammation mediators in a tight serum protein interactome was a biomarker of sustained XOI-based ULT that effectively reduced serum urate and gout flares. Monitoring of the serum and PBMC proteome, including for changes in the complement pathway could help determine onset and targets of anti-inflammatory changes in response to effective, sustained XOI-based ULT.Trial Registration: ClinicalTrials.gov Identifier: NCT02579096.
PubMed: 38260556
DOI: 10.21203/rs.3.rs-3770277/v1 -
Frontiers in Pharmacology 2023This study investigates the impact of xanthine oxidase inhibitors (XOI) on mortality in patients with cardiovascular diseases. XOI withdrawal has been reported to...
This study investigates the impact of xanthine oxidase inhibitors (XOI) on mortality in patients with cardiovascular diseases. XOI withdrawal has been reported to increased mortality risk due to rapid adenosine triphosphate (ATP) deficiency. This study aims to determine whether XOI treatment reduces mortality and whether XOI withdrawal increases mortality. This is a real-world database study using the Japanese Registry of All Cardiac and Vascular Diseases (J-ROAD). We analyzed 1,648,891 hospitalized patients aged 20-90 with acute coronary syndrome or heart failure. In the first study, mortality rates were compared between patients without urate-lowering agents (n = 1,292,486) and those with XOI agents (n = 315,388, excluding 41,017 on other urate-lowering agents). In the second study, mortality rates were compared between the XOI continuous medication group (n = 226,261) and the XOI withdrawal group (n = 89,127). After multiple adjustments, XOI treatment group showed significantly lower mortality compared with that without any urate-lowering agent (odds ratio (OR), 0.576, 95% confidence interval (CI), 0.567-0.587, < .001). In the sub-analysis, the group with allopurinol (OR, 0.578; 95% CI, 0.557-0.600), febuxostat (OR, 0.610; 95% CI, 0.599-0.622), and topiroxostat (HR, 0.545; 95% CI, 0.473-0.628) showed lower OR of mortality compared with that without any urate-lowering agent. XOI withdrawal group led to significantly higher death rates compared to XOI continuous group (19.8% vs. 0.03%; < .001). XOI treatment for patients with cardiovascular diseases is associated with reduced mortality. Conversely, XOI withdrawal is linked to elevated mortality risk. This emphasizes the importance of both prescribing and discontinuing XOI carefully to optimize patient outcomes.
PubMed: 38259292
DOI: 10.3389/fphar.2023.1289386