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Annals of the Rheumatic Diseases May 2024To investigate gout flare rates based on repeated serum urate (SU) measurements in a randomised controlled trial of urate-lowering therapy (ULT), accounting for dropout...
Identifying the association between serum urate levels and gout flares in patients taking urate-lowering therapy: a post hoc cohort analysis of the CARES trial with consideration of dropout.
OBJECTIVE
To investigate gout flare rates based on repeated serum urate (SU) measurements in a randomised controlled trial of urate-lowering therapy (ULT), accounting for dropout and death.
METHODS
We performed a secondary analysis using data from Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout, which randomised participants to febuxostat or allopurinol, titrated to target SU <6 mg/dL with flare prophylaxis for 6 months. SU was categorised as ≤3.9, 4.0-5.9, 6.0-7.9, 8.0-9.9 or ≥ 10 mg/dL at each 3-6 month follow-up. The primary outcome was gout flare. Poisson regression models, adjusted for covariates and factors related to participant retention versus dropout, estimated gout flare incidence rate ratios by time-varying SU category.
RESULTS
Among 6183 participants, the median age was 65 years and 84% were male. Peak gout flare rates for all SU categories were observed in months 0-6, coinciding with the initiation of ULT and months 6-12 after stopping prophylaxis. Flare rates were similar across SU groups in the initial year of ULT. During months 36-72, a dose-response relationship was observed between the SU category and flare rate. Lower flare rates were observed when SU ≤3.9 mg/dL and greater rates when SU ≥10 mg/dL, compared with SU 4.0-5.9 mg/dL (p for trend <0.01).
CONCLUSION
Gout flare rates were persistently higher when SU ≥6 mg/dL after the first year of ULT after accounting for censoring. The spike in flares in all categories after stopping prophylaxis suggests a longer duration of prophylaxis may be warranted.
PubMed: 38724073
DOI: 10.1136/ard-2024-225761 -
Brain Research Bulletin Jul 2024Epilepsy is a common neurological disease characterized by the recurrent, paroxysmal, and unprovoked seizures. It has been shown that hyperuricemia enhances and... (Review)
Review
Epilepsy is a common neurological disease characterized by the recurrent, paroxysmal, and unprovoked seizures. It has been shown that hyperuricemia enhances and associated with the development and progression of epilepsy through induction of inflammation and oxidative stress. In addition, uric acid is released within the brain and contributes in the development of neuronal hyperexcitability and epileptic seizure. Brain uric acid acts as damage associated molecular pattern (DAMP) activates the immune response and induce the development of neuroinflammation. Therefore, inhibition of xanthine oxidase by allopurinol may reduce hyperuricemia-induced epileptic seizure and associated oxidative stress and inflammation. However, the underlying mechanism of allopurinol in the epilepsy was not fully elucidated. Therefore, this review aims to revise from published articles the link between hyperuricemia and epilepsy, and how allopurinol inhibits the development of epileptic seizure.
Topics: Hyperuricemia; Allopurinol; Humans; Epilepsy; Animals; Oxidative Stress; Uric Acid; Xanthine Oxidase; Brain
PubMed: 38723694
DOI: 10.1016/j.brainresbull.2024.110973 -
Journal of Pharmaceutical and... Aug 2024A high-performance liquid chromatography (HPLC) method was developed for the analysis of Allopurinol and its Ph.Eur. impurities using a porous graphitic carbon (PGC)...
Linear solvent strength model on porous graphitic carbon stationary phase using high temperature liquid chromatographic method for allopurinol related substances analysis.
A high-performance liquid chromatography (HPLC) method was developed for the analysis of Allopurinol and its Ph.Eur. impurities using a porous graphitic carbon (PGC) stationary phase. Retention behavior of solutes was studied across a wide temperature range (30-90 °C) and various gradient times (5-20 min). Analysis of the data revealed distinct retention mechanisms between reversed-phase and PGC phases. However, it was proved that the retention of Allopurinol and its Ph.Eur. impurities on PGC stationary phase can be effectively modeled using the linear solvent strength (LSS) theory. This allows for the utilization of LSS-based method development software to optimize methods under these conditions. By using commercial chromatographic modeling software, separation of Allopurinol and Ph.Eur. impurities was optimized within a large design space. At the optimized operating conditions (pH = 2.0, tG = 6 min, T = 60 °C), all solutes were separated within 6 min with baseline resolution. Comparison between predicted and experimentally measured chromatograms further confirmed the applicability of LSS theory in developing analytical methods for PGC-based HPLC systems. The presented approach offers a general framework for method development on PGC phases.
Topics: Chromatography, High Pressure Liquid; Graphite; Solvents; Allopurinol; Porosity; Temperature; Drug Contamination; Hot Temperature
PubMed: 38723557
DOI: 10.1016/j.jpba.2024.116200 -
Haematologica May 2024Not available.
Not available.
PubMed: 38721742
DOI: 10.3324/haematol.2024.285080 -
CNS & Neurological Disorders Drug... May 2024In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis...
BACKGROUND
In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition.
OBJECTIVE
This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis.
METHODS
Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days.
RESULTS
Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified.
CONCLUSION
In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.
PubMed: 38712373
DOI: 10.2174/0118715273282363240415045927 -
ELife May 2024Adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) are two structurally related enzymes involved in purine recycling in...
Adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) are two structurally related enzymes involved in purine recycling in humans. Inherited mutations that suppress HGPRT activity are associated with Lesch-Nyhan disease (LND), a rare X-linked metabolic and neurological disorder in children, characterized by hyperuricemia, dystonia, and compulsive self-injury. To date, no treatment is available for these neurological defects and no animal model recapitulates all symptoms of LND patients. Here, we studied LND-related mechanisms in the fruit fly. By combining enzymatic assays and phylogenetic analysis, we confirm that no HGPRT activity is expressed in , making the APRT homolog (Aprt) the only purine-recycling enzyme in this organism. Whereas APRT deficiency does not trigger neurological defects in humans, we observed that mutants show both metabolic and neurobehavioral disturbances, including increased uric acid levels, locomotor impairments, sleep alterations, seizure-like behavior, reduced lifespan, and reduction of adenosine signaling and content. Locomotor defects could be rescued by Aprt re-expression in neurons and reproduced by knocking down selectively in the protocerebral anterior medial (PAM) dopaminergic neurons, the mushroom bodies, or glia subsets. Ingestion of allopurinol rescued uric acid levels in -deficient mutants but not neurological defects, as is the case in LND patients, while feeding adenosine or -methyladenosine (mA) during development fully rescued the epileptic behavior. Intriguingly, pan-neuronal expression of an LND-associated mutant form of human HGPRT (I42T), but not the wild-type enzyme, resulted in early locomotor defects and seizure in flies, similar to deficiency. Overall, our results suggest that could be used in different ways to better understand LND and seek a cure for this dramatic disease.
Topics: Animals; Drosophila melanogaster; Lesch-Nyhan Syndrome; Purines; Disease Models, Animal; Behavior, Animal; Hypoxanthine Phosphoribosyltransferase; Drosophila Proteins; Locomotion
PubMed: 38700995
DOI: 10.7554/eLife.88510 -
European Journal of Medicinal Chemistry May 2024Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and...
Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC value of 0.13 μM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC = 2.93 μM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.
Topics: Xanthine Oxidase; Drug Design; Structure-Activity Relationship; Enzyme Inhibitors; Isoxazoles; Carboxylic Acids; Molecular Structure; Humans; Molecular Docking Simulation; Indoles; Dose-Response Relationship, Drug
PubMed: 38691887
DOI: 10.1016/j.ejmech.2024.116443 -
Cellular and Molecular Biology... Apr 2024This study aimed to experimentally compare the uric acid-lowering effect and renal protection of Yiqing Fang in a rat model of hyperuricemia. Additionally, we used...
This study aimed to experimentally compare the uric acid-lowering effect and renal protection of Yiqing Fang in a rat model of hyperuricemia. Additionally, we used network pharmacology to predict the potential active components, targets, and pathways of Yiqing Fang. Male SD rats were randomly divided into control, model, Yiqing Fang, allopurinol, and probenecid groups. Serum creatinine (Scr), blood urea nitrogen (BUN), serum uric acid (UA), alanine transaminase (ALT), complete blood count, and urinary NAG enzyme levels were measured. Standard pathology and electron microscopy samples were prepared from the left kidney to observe renal pathological changes, renal fibrosis, and collagen III expression levels. In addition, we employed network pharmacology to investigate the molecular mechanisms and pathways of Yiqing Fang. The Yiqing Fang group showed significantly lower levels of Scr, BUN, UA, ALT, urinary NAG enzyme, complete blood count, and liver function tests compared to the model group (P < 0.05). Furthermore, both the Yiqing Fang and allopurinol groups exhibited significant reductions in renal pathological changes compared to the model group, along with decreased expression of collagen III. Network pharmacology analysis identified a total of 27 specific sites related to hyperuricemia. The main active components were predicted to include quercetin, berberine, beta-sitosterol, epimedin C, and dioscin. The primary target sites were predicted to include TNF, IL-6, IL-17, IL-1B, and VEGFA. Yiqing Fang may exert its effects through regulation of drug response, urate metabolism, purine compound absorption, inflammation response, lipopolysaccharide response, cytokine activity, and antioxidant activity. These effects may be mediated through signaling pathways such as IL-17, HIF-1, and AGE-RAGE. Yiqing Fang offers potential as a treatment for hyperuricemia due to its multiple active components, targeting of various sites, and engagement of multiple pathways.
Topics: Animals; Hyperuricemia; Male; Rats, Sprague-Dawley; Kidney; Drugs, Chinese Herbal; Uric Acid; Rats; Disease Models, Animal; Network Pharmacology; Creatinine; Blood Urea Nitrogen
PubMed: 38678602
DOI: 10.14715/cmb/2024.70.4.34 -
Toxicology in Vitro : An International... Jun 2024Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome,...
Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.
Topics: Humans; Molecular Docking Simulation; Microsomes, Liver; Carboxylic Ester Hydrolases; Gout Suppressants; Enzyme Inhibitors; Carboxylesterase
PubMed: 38670244
DOI: 10.1016/j.tiv.2024.105833