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Clinical and Translational Science Mar 2024The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a... (Meta-Analysis)
Meta-Analysis
The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a systematic review and meta-analysis to compare the CV safety profiles of febuxostat with allopurinol in Asian patients with hyperuricemia. A total of 13 studies were included. On the basis of the pooled results of cohort studies, febuxostat users were at a significantly higher risk for acute coronary syndrome (ACS; hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.03-1.09, p < 0.01), atrial fibrillation (HR: 1.19, 95% CI: 1.05-1.35, p < 0.01) than allopurinol users, whereas no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR: 1.07, 95% CI: 0.98-1.16, p = 0.13), and stroke (HR: 0.96, 95% CI: 0.91-1.01, p = 0.13). Nevertheless, that difference in results of acute decompensated heart failure (ADHF; HR: 0.73, 95% CI: 0.35-1.53, p = 0.40) and all-cause death (HR = 0.86, 95% CI: 0.49-1.51, p = 0.60) was not significant based on randomized controlled trials. In the Chinese subgroup, febuxostat could increase the risk of ADHF (HR: 1.22, 95% CI: 1.01-1.48, p < 0.05), CV death (HR: 1.25, 95% CI: 1.03-1.50, p < 0.05), and all-cause mortality (HR: 1.07, 95% CI: 1.01-1.14, p < 0.05) compared to allopurinol. In conclusion, the use of febuxostat, compared with allopurinol among Asian patients, was associated with a significantly increased risk of adverse CV events.
Topics: Humans; Allopurinol; Febuxostat; Hyperuricemia; Gout Suppressants; Cardiovascular Diseases; Gout; Treatment Outcome
PubMed: 38488426
DOI: 10.1111/cts.13757 -
Cells Feb 2024Inflammatory bowel disease (IBD) is marked by a state of chronic energy deficiency that limits gut tissue wound healing. This energy shortfall is partially due to...
Inflammatory bowel disease (IBD) is marked by a state of chronic energy deficiency that limits gut tissue wound healing. This energy shortfall is partially due to microbiota dysbiosis, resulting in the loss of microbiota-derived metabolites, which the epithelium relies on for energy procurement. The role of microbiota-sourced purines, such as hypoxanthine, as substrates salvaged by the colonic epithelium for nucleotide biogenesis and energy balance, has recently been appreciated for homeostasis and wound healing. Allopurinol, a synthetic hypoxanthine isomer commonly prescribed to treat excess uric acid in the blood, inhibits the degradation of hypoxanthine by xanthine oxidase, but also inhibits purine salvage. Although the use of allopurinol is common, studies regarding how allopurinol influences the gastrointestinal tract during colitis are largely nonexistent. In this work, a series of and experiments were performed to dissect the relationship between allopurinol, allopurinol metabolites, and colonic epithelial metabolism and function in health and during disease. Of particular significance, the investigation identified that a therapeutically relevant allopurinol dose shifts adenylate and creatine metabolism, leading to AMPK dysregulation and disrupted proliferation to attenuate wound healing and increased tissue damage in murine experimental colitis. Collectively, these findings underscore the importance of purine salvage on cellular metabolism and gut health in the context of IBD and provide insight regarding the use of allopurinol in patients with IBD.
Topics: Humans; Mice; Animals; Allopurinol; Purines; Hypoxanthine; Colitis; Inflammatory Bowel Diseases
PubMed: 38474337
DOI: 10.3390/cells13050373 -
Joint Bone Spine Mar 2024Monosodium-urate (MSU) crystal deposits can be visualized and quantified with dual-energy CT (DECT). Pegloticase lowers serum urate (SU) in uncontrolled gout patients,...
Monosodium urate crystal depletion and bone erosion remodeling during pegloticase treatment in patients with uncontrolled gout: Exploratory dual-energy computed tomography findings from MIRROR RCT.
OBJECTIVE
Monosodium-urate (MSU) crystal deposits can be visualized and quantified with dual-energy CT (DECT). Pegloticase lowers serum urate (SU) in uncontrolled gout patients, with methotrexate (MTX) co-therapy recommended to increase SU-lowering response rate and decrease infusion reaction risk. The literature on serial DECT-imaging during pegloticase+MTX co-therapy is sparse, with only 2 prior cases of rapid MSU deposition depletion with subsequent bone-erosion remodeling reported from a small open-label trial. Here, we report DECT findings during pegloticase treatment in a larger number of patients from a randomized controlled trial to confirm bone-erosion remodeling that follows MSU depletion with pegloticase. The influence of length-of-therapy is also explored.
METHODS
Patients received pegloticase (8mg every 2weeks)+MTX (15mg/week orally) or pegloticase+placebo (PBO) during the MIRROR RCT trial. A subset underwent DECT-imaging on Day1 (first pegloticase infusion) and at Weeks 14, 24, and 52. Patients with paired baseline-Week 52 images were included. Imaged regions with baseline MSU-crystal volume (V)<0.5cm were excluded to minimize artifact contributions. V and bone-erosion remodeling were assessed.
RESULTS
Eight patients (6 MTX, 2 PBO) were included. Included patients had received 52weeks (5 MTX), 42weeks (1 PBO), and 6weeks (1 MTX, 1 PBO) of pegloticase therapy. Patients who prematurely discontinued pegloticase maintained SU<6mg/dL on allopurinol (n=2)/febuxostat (n=1). At Week 52, V had markedly decreased in both the pegloticase+MTX and pegloticase+PBO treatment groups, with faster depletion during pegloticase therapy. Bone-erosion remodeling was observed in 29/42 (69%) evaluated erosions: 29 (69%) size decrease, 4 (9.5%) recortication, 3 (7.1%) new bone formation.
CONCLUSION
Rapid V depletion during pegloticase therapy was observed with concomitant bone remodeling within 1year. Following pegloticase discontinuation, V reduction slowed or stopped even when SU was maintained<6mg/dL with oral ULT.
CLINICAL TRIAL REGISTRATION
NCT03994731.
PubMed: 38447697
DOI: 10.1016/j.jbspin.2024.105715 -
Saudi Pharmaceutical Journal : SPJ :... Apr 2024Xanthine oxidase (XO) has been widely recognized as a pivotal enzyme in developing hyperuricemia, primarily contributing to the excessive production of uric acid during...
Xanthine oxidase (XO) has been widely recognized as a pivotal enzyme in developing hyperuricemia, primarily contributing to the excessive production of uric acid during purine metabolism in the liver. One of the standard treatment approaches involves reducing uric acid levels by inhibiting XO activity. In this study, the leaf extract of , traditionally used in folk medicine, was found to inhibit XO activity in the ethyl acetate and butanol fractions at a concentration of 100 µg/mL, their values were 78.57 ± 3.85 % (IC = 55.93 ± 5.73 µg/ml) and 69.43 ± 8.68 % (IC = 70.17 ± 7.98 µg/ml), respectively. The potential XO inhibitory components were isolated by bioactivity assays and the HR-ESI-MS and NMR spectra system. The main constituents of leaf extracts of , six compounds, namely 4-methoxycinnamic acid (), -3,4-dimethoxycinnamic acid (), -coumaric acid (), martynoside (), 6-O-(-methoxy--cinnamoyl)-ajugol (), and scolymoside (), were identified as potent XO inhibitors with IC values ranging from 19.34 ± 1.63 μM to 64.50 ± 0.94 μM. The enzyme kinetics indicated that compounds -, , and displayed competitive inhibition like allopurinol, while compound displayed a mixed-type inhibition. Computational studies corroborated these experimental results, highlighting the interactions between potential metabolites and XO enzyme. The hydrogen bonds played crucial roles in the binding interaction, especially, scolymoside () forms a hydrogen bond with Mos3004, exhibited the lowest binding energy (-18.3286 kcal/mol) corresponding to the lowest IC (19.34 ± 1.63 μM). Furthermore, nine compounds were isolated for the first time from this plant. , and its constituents possess the potential to modulate the xanthine oxidase enzyme involved in metabolism.
PubMed: 38439949
DOI: 10.1016/j.jsps.2024.101980 -
Journal of Human Hypertension Apr 2024Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it... (Randomized Controlled Trial)
Randomized Controlled Trial
Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.
Topics: Humans; Blood Pressure; Ischemic Attack, Transient; Allopurinol; Hypertension; Ischemic Stroke; Uric Acid; Risk Factors; Blood Pressure Monitoring, Ambulatory
PubMed: 38438602
DOI: 10.1038/s41371-024-00906-5 -
Molecular and Biochemical Parasitology Jun 2024Trypanosoma cruzi is a protozoan parasite and the etiological agent of Chagas disease, a debilitating and sometimes fatal disease that continues to spread to new areas....
Mapping the transporter-substrate interactions of the Trypanosoma cruzi NB1 nucleobase transporter reveals the basis for its high affinity and selectivity for hypoxanthine and guanine and lack of nucleoside uptake.
Trypanosoma cruzi is a protozoan parasite and the etiological agent of Chagas disease, a debilitating and sometimes fatal disease that continues to spread to new areas. Yet, Chagas disease is still only treated with two related nitro compounds that are insufficiently effective and cause severe side effects. Nucleotide metabolism is one of the known vulnerabilities of T. cruzi, as they are auxotrophic for purines, and nucleoside analogues have been shown to have genuine promise against this parasite in vitro and in vivo. Since purine antimetabolites require efficient uptake through transporters, we here report a detailed characterisation of the T. cruzi NB1 nucleobase transporter with the aim of elucidating the interactions between TcrNB1 and its substrates and finding the positions that can be altered in the design of novel antimetabolites without losing transportability. Systematically determining the inhibition constants (K) of purine analogues for TcrNB1 yielded their Gibbs free energy of interaction, ΔG. Pairwise comparisons of substrate (hypoxanthine, guanine, adenine) and analogues allowed us to determine that optimal binding affinity by TcrNB1 requires interactions with all four nitrogen residues of the purine ring, with N1 and N9, in protonation state, functioning as presumed hydrogen bond donors and unprotonated N3 and N7 as hydrogen bond acceptors. This is the same interaction pattern as we previously described for the main nucleobase transporters of Trypanosoma brucei spp. and Leishmania major and makes it the first of the ENT-family genes that is functionally as well as genetically conserved between the three main kinetoplast pathogens.
Topics: Trypanosoma cruzi; Guanine; Hypoxanthine; Protozoan Proteins; Nucleobase Transport Proteins; Biological Transport; Substrate Specificity; Protein Binding; Nucleosides
PubMed: 38401850
DOI: 10.1016/j.molbiopara.2024.111616 -
Children (Basel, Switzerland) Jan 2024A 13-year-old male undergoing maintenance chemotherapy with methotrexate and 6-mercaptopurine (6MP), for very high-risk B-cell acute lymphoblastic leukemia (ALL),...
A 13-year-old male undergoing maintenance chemotherapy with methotrexate and 6-mercaptopurine (6MP), for very high-risk B-cell acute lymphoblastic leukemia (ALL), presented with vomiting due to severe hypoglycemia with metabolic acidosis. While his laboratory values were concerning for a critically ill child, the patient was relatively well appearing. Hypoglycemia is a rare but serious side effect of 6MP with an unexpectedly variable presentation; therefore, a high index of suspicion is needed for its prompt detection and treatment. This patient also had severe metabolic acidosis, likely secondary to hypoglycemia, creating a serious clinical picture despite a well-appearing child. This example of incongruity between laboratory tests and clinical appearance adds nuance to the existing literature. Moreover, although 6MP-associated hypoglycemia is rare, it may be more prevalent than the literature suggests, as symptoms of hypoglycemia-nausea, vomiting, and somnolence-mirror common chemotherapy side effects. 6MP-induced hypoglycemia can be ameliorated with the addition of allopurinol to shunt metabolism in favor of the production of therapeutic metabolites over hepatotoxic metabolites. Additionally, a morning administration of 6MP and frequent snacks may also help to prevent hypoglycemia. Overall, this case adds to the literature of unusual reactions to 6MP including hypoglycemia in an older child without traditional risk factors.
PubMed: 38397272
DOI: 10.3390/children11020160 -
Metabolites Feb 2024(Sweet) Nakai () fruit has medicinal and food applications and exhibits beneficial pharmacological properties. This study aimed to explore the hypouricemic effect of...
(Sweet) Nakai () fruit has medicinal and food applications and exhibits beneficial pharmacological properties. This study aimed to explore the hypouricemic effect of fruit extracts on hyperuricemic rats and uncover potential protective mechanisms. The rats were given hypoxanthine (HX, 100 mg/kg) and potassium oxonate (PO, 300 mg/kg) for 14 days to induce hyperuricemia. Subsequently, the rats were orally administered fruits total extract (CSFTE, 250, 500, and 1000 mg/kg) and allopurinol (AP, 10 mg/kg) one hour after exposure to HX and PO. The results showed that CSFTE had significant xanthine oxidase (XOD) inhibitory activity in vitro (IC value of 334.2 μg/mL) and exhibited hypouricemic effects in vivo, reducing uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN) levels in serum. CSFTE increased UA excretion through the regulation of URAT1, GLUT9, OAT1, and OAT3 protein expression in the kidneys of hyperuricemic rats. Additionally, CSFTE (500 and 1000 mg/kg) was more effective than AP in improving renal injury and protecting kidney function in hyperuricemic rats. Our study demonstrated that CSFTE effectively reduced UA levels and protected the kidneys by inhibiting XOD expression in vitro and regulating UA, CRE, BUN, URAT1, GLUT9, OAT1, and OAT3 proteins in vivo.
PubMed: 38393010
DOI: 10.3390/metabo14020117 -
Journal of Functional Biomaterials Jan 2024This review aimed at searching literature for data regarding the inflammasomes' involvement in the pathogenesis of oral diseases (mainly periodontitis) and general... (Review)
Review
This review aimed at searching literature for data regarding the inflammasomes' involvement in the pathogenesis of oral diseases (mainly periodontitis) and general pathologies, including approaches to control inflammasome-related pathogenic mechanisms. The inflammasomes are part of the innate immune response that activates inflammatory caspases by canonical and noncanonical pathways, to control the activity of Gasdermin D. Once an inflammasome is activated, pro-inflammatory cytokines, such as interleukins, are released. Thus, inflammasomes are involved in inflammatory, autoimmune and autoinflammatory diseases. The review also investigated novel therapies based on the use of phytochemicals and pharmaceutical substances for inhibiting inflammasome activity. Pharmaceutical substances can control the inflammasomes by three mechanisms: inhibiting the intracellular signaling pathways (Allopurinol and SS-31), blocking inflammasome components (VX-765, Emricasan and VX-740), and inhibiting cytokines mediated by the inflammasomes (Canakinumab, Anakinra and Rilonacept). Moreover, phytochemicals inhibit the inflammasomes by neutralizing reactive oxygen species. Biomaterials functionalized by the adsorption of therapeutic agents onto different nanomaterials could represent future research directions to facilitate multimodal and sequential treatment in oral pathologies.
PubMed: 38391885
DOI: 10.3390/jfb15020032 -
BMC Nephrology Feb 2024The composition of organ preservation solutions is crucial for maintaining graft integrity and early graft function after transplantation. The aim of this study is to...
BACKGROUND
The composition of organ preservation solutions is crucial for maintaining graft integrity and early graft function after transplantation. The aim of this study is to compare new organ preservation solution PERLA® with the gold standard preservation solution University of Wisconsin (UW) regarding oxidative stress and early graft injury.
METHODS
In order to assess oxidative stress after cold storage, kidney grafts have been preserved for 18 h at 4° C in either UW solution or PERLA® solution and then assessed for oxidative stress injury (protocol 1). To assess kidney injuries and oxidative stress after reperfusion, rat kidneys were harvested, stored in cold UW or in PERLA® solutions for 18 h at 4 °C and then transplanted heterotopically for 6 h (protocol 2). PERLA® is a high Na/low K solution including PEG-35 (1 g/L), trimetazidine (1 µM), carvedilol (10 µM) and tacrolimus (5 µM).
RESULTS
Our results showed that preservation of kidneys in PERLA® solution significantly attenuates oxidative stress parameters after cold storage and reperfusion. We found a significant decrease in oxidative damage indicators (MDA, CD and CP) and a significant increase in antioxidant indicators (GPx, GSH, CAT, SOD and PSH). Moreover, PERLA® solution decreased kidney injury after reperfusion (creatinine, LDH and uric acid).
CONCLUSION
PERLA® solution was more effective than UW storage solution in preserving rat's kidney grafts.
Topics: Humans; Rats; Animals; Kidney Transplantation; Reperfusion Injury; Organ Preservation Solutions; Kidney; Allopurinol; Oxidative Stress; Adenosine; Glutathione; Insulin; Raffinose
PubMed: 38389057
DOI: 10.1186/s12882-024-03488-z