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1.
Pharmacogenomics ; 25(10-11): 479-494, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39347581

RESUMEN

Aim: To summarize the effects of single nucleotide polymorphisms (SNPs) on the pharmacokinetics of allopurinol to control uric acid levels.Methods: A comprehensive search was conducted in PubMed, Web of Science and Scopus databases from inception to January 2024, includes 17 articles focusing on SNPs and pharmacokinetics of allopurinol and oxypurinol.Results: A total of 11 SNPs showed a significant association with pharmacokinetics of allopurinol and oxypurinol, as well as their potential clinical implications.Conclusion: SNPs in ATP-binding cassette super-family G member 2 (ABCG2), solute carrier family 2 member 9 (SLC2A9), solute carrier family 17 member 1 (SLC17A1), solute carrier family 22 member 12 (SLC22A12), solute carrier family 22 member 13 (SLC22A13) and PDZ domain containing 1 (PDZK1) genes were associated with allopurinol clearance, while SNPs in aldehyde oxidase 1 (AOX1) genes involved in metabolism of allopurinol. SNPs in gremlin 2, DAN family BMP antagonist (GREM2) gene impacted uric acid control, but the specific mechanism governing the expression of GREM2 remains unknown. Our study indicated that the identified SNPs show contradictory effects, reflecting inconsistencies and differences observed across various studies.


[Box: see text].


Asunto(s)
Alopurinol , Polimorfismo de Nucleótido Simple , Ácido Úrico , Alopurinol/farmacocinética , Alopurinol/uso terapéutico , Humanos , Polimorfismo de Nucleótido Simple/genética , Ácido Úrico/sangre , Supresores de la Gota/farmacocinética , Supresores de la Gota/uso terapéutico
2.
Cureus ; 16(7): e64654, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39149682

RESUMEN

Allopurinol lowers urate production through the inhibition of xanthine oxidase. It is oxidatively hydroxylated to oxypurinol and is the most prescribed medication for gout treatment. Although it has a beneficial effect in the treatment of this common disease, like many medications, it is also known for having numerous adverse effects. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), diseases that exist on a spectrum, are two of the most dangerous adverse effects associated with allopurinol use. These immune-mediated disease processes involve almost every organ system. They are essential to recognize as early as possible, as they could potentially be deadly, requiring cessation of the medication with initial signs of rash or other early manifestations of SJS/TEN. One major consideration in the increased risk of allopurinol-mediated or modulated SJS/TEN is the need to have a lower dose in the setting of renal disease. The purpose of this review is not only to examine the involvement of allopurinol in SJS/TEN but also to provide detailed information about the drug, allopurinol, and general features and characteristics of SJS/TEN and other associated drug reactions.

3.
Front Immunol ; 15: 1369116, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38711505

RESUMEN

Objective: Previous research has partially revealed distinct gut microbiota in ankylosing spondylitis (AS). In this study, we performed non-targeted fecal metabolomics in AS in order to discover the microbiome-metabolome interface in AS. Based on prospective cohort studies, we further explored the impact of the tumor necrosis factor inhibitor (TNFi) on the gut microbiota and metabolites in AS. Methods: To further understand the gut microbiota and metabolites in AS, along with the influence of TNFi, we initiated a prospective cohort study. Fecal samples were collected from 29 patients with AS before and after TNFi therapy and 31 healthy controls. Metagenomic and metabolomic experiments were performed on the fecal samples; moreover, validation experiments were conducted based on the association between the microbiota and metabolites. Results: A total of 7,703 species were annotated using the metagenomic sequencing system and by profiling the microbial community taxonomic composition, while 50,046 metabolites were identified using metabolite profiling. Differential microbials and metabolites were discovered between patients with AS and healthy controls. Moreover, TNFi was confirmed to partially restore the gut microbiota and the metabolites. Multi-omics analysis of the microbiota and metabolites was performed to determine the associations between the differential microbes and metabolites, identifying compounds such as oxypurinol and biotin, which were correlated with the inhibition of the pathogenic bacteria Ruminococcus gnavus and the promotion of the probiotic bacteria Bacteroides uniformis. Through experimental studies, the relationship between microbes and metabolites was further confirmed, and the impact of these two types of microbes on the enterocytes and the inflammatory cytokine interleukin-18 (IL-18) was explored. Conclusion: In summary, multi-omics exploration elucidated the impact of TNFi on the gut microbiota and metabolites and proposed a novel therapeutic perspective: supplementation of compounds to inhibit potential pathogenic bacteria and to promote potential probiotics, therefore controlling inflammation in AS.


Asunto(s)
Heces , Microbioma Gastrointestinal , Metaboloma , Probióticos , Espondilitis Anquilosante , Humanos , Espondilitis Anquilosante/microbiología , Espondilitis Anquilosante/metabolismo , Espondilitis Anquilosante/inmunología , Masculino , Femenino , Adulto , Heces/microbiología , Metagenómica/métodos , Persona de Mediana Edad , Estudios Prospectivos , Metabolómica , Bacterias/metabolismo , Bacterias/clasificación , Bacterias/aislamiento & purificación , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/farmacología
4.
Am J Physiol Renal Physiol ; 326(6): F1004-F1015, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38634129

RESUMEN

Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were two aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight, and cyst index. Mechanisms of increased cyst growth that were investigated were proinflammatory cytokines, the inflammasome, and crystal deposition in the kidney. Oxonic acid resulted in an increase in proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.NEW & NOTEWORTHY This is the first reported study of uric acid measurements and xanthine oxidase inhibition in polycystic kidney disease (PKD) rodents. Raising serum uric acid with a uricase inhibitor resulted in increased kidney weight and cyst index in Pkd1RC/RC mice and PCK rats, elevated levels of proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice, and no uric acid crystal deposition or activation of the caspase-1 inflammasome in the kidney.


Asunto(s)
Modelos Animales de Enfermedad , Riñón , Enfermedades Renales Poliquísticas , Urato Oxidasa , Ácido Úrico , Animales , Ácido Úrico/sangre , Enfermedades Renales Poliquísticas/patología , Enfermedades Renales Poliquísticas/metabolismo , Enfermedades Renales Poliquísticas/tratamiento farmacológico , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Oxipurinol/farmacología , Ácido Oxónico/farmacología , Inhibidores Enzimáticos/farmacología , Ratas , Femenino , Inflamasomas/metabolismo , Citocinas/metabolismo , Citocinas/sangre , Ratones , Canales Catiónicos TRPP/genética , Canales Catiónicos TRPP/metabolismo , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Ratas Sprague-Dawley , Ratones Endogámicos C57BL
5.
Nephrology (Carlton) ; 29(8): 547-550, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38626950

RESUMEN

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.


Asunto(s)
Supresores de la Gota , Gota , Oxipurinol , Diálisis Peritoneal , Ácido Úrico , Humanos , Ácido Úrico/sangre , Gota/tratamiento farmacológico , Gota/sangre , Masculino , Oxipurinol/farmacocinética , Supresores de la Gota/farmacocinética , Supresores de la Gota/uso terapéutico , Persona de Mediana Edad , Femenino , Anciano , Alopurinol/uso terapéutico , Alopurinol/farmacocinética , Eliminación Renal , Semivida , Soluciones para Diálisis/farmacocinética
6.
J Biol Chem ; 299(9): 105189, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37625592

RESUMEN

Xanthine oxidoreductase is a metalloenzyme that catalyzes the final steps in purine metabolism by converting hypoxanthine to xanthine and then uric acid. Allopurinol, an analog of hypoxanthine, is widely used as an antigout drug, as xanthine oxidoreductase-mediated metabolism of allopurinol to oxypurinol leads to oxypurinol rotation in the enzyme active site and reduction of the molybdenum Mo(VI) active center to Mo(IV), inhibiting subsequent urate production. However, when oxypurinol is administered directly to a mouse model of hyperuricemia, it yields a weaker urate-lowering effect than allopurinol. To better understand its mechanism of inhibition and inform patient dosing strategies, we performed kinetic and structural analyses of the inhibitory activity of oxypurinol. Our results demonstrated that oxypurinol was less effective than allopurinol both in vivo and in vitro. We show that upon reoxidation to Mo(VI), oxypurinol binding is greatly weakened, and reduction by xanthine, hypoxanthine, or allopurinol is required for reformation of the inhibitor-enzyme complex. In addition, we show oxypurinol only weakly inhibits the conversion of hypoxanthine to xanthine and is therefore unlikely to affect the feedback inhibition of de novo purine synthesis. Furthermore, we observed weak allosteric inhibition of purine nucleoside phosphorylase by oxypurinol which has potentially adverse effects for patients. Considering these results, we propose the single-dose method currently used to treat hyperuricemia can result in unnecessarily high levels of allopurinol. While the short half-life of allopurinol in blood suggests that oxypurinol is responsible for enzyme inhibition, we anticipate multiple, smaller doses of allopurinol would reduce the total allopurinol patient load.

7.
Allergy ; 78(11): 2980-2993, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37452515

RESUMEN

Allopurinol (ALP) is a successful drug used in the treatment of gout. However, this drug has been implicated in hypersensitivity reactions that can cause severe to life-threatening reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Individuals who carry the human leukocyte antigen (HLA)-B*58:01 allotype are at higher risk of experiencing a hypersensitivity reaction (odds ratios ranging from 5.62 to 580.3 for mild to severe reactions, respectively). In addition to the parent drug, the metabolite oxypurinol (OXP) is implicated in triggering T cell-mediated immunopathology via a labile interaction with HLA-B*58:01. To date, there has been limited information regarding the T-cell receptor (TCR) repertoire usage of reactive T cells in patients with ALP-induced SJS or TEN and, in particular, there are no reports examining paired αßTCRs. Here, using in vitro drug-treated PBMCs isolated from both resolved ALP-induced SJS/TEN cases and drug-naïve healthy donors, we show that OXP is the driver of CD8+ T cell-mediated responses and that drug-exposed memory T cells can exhibit a proinflammatory immunophenotype similar to T cells described during active disease. Furthermore, this response supported the pharmacological interaction with immune receptors (p-i) concept by showcasing (i) the labile metabolite interaction with peptide/HLA complexes, (ii) immunogenic complex formation at the cell surface, and (iii) lack of requirement for antigen processing to elicit drug-induced T cell responsiveness. Examination of paired OXP-induced αßTCR repertoires highlighted an oligoclonal and private clonotypic profile in both resolved ALP-induced SJS/TEN cases and drug-naïve healthy donors.


Asunto(s)
Alopurinol , Síndrome de Stevens-Johnson , Humanos , Alopurinol/efectos adversos , Oxipurinol/farmacología , Síndrome de Stevens-Johnson/genética , Linfocitos T CD8-positivos , Antígenos HLA-B/genética
8.
Front Med (Lausanne) ; 10: 1030577, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36968831

RESUMEN

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI) by increasing oxidative stress, inflammatory responses, and tubular cell death. Oxypurinol, an active metabolite of allopurinol, is a potent anti-inflammatory and antioxidant agent. To investigate the therapeutic potential and underlying mechanism of oxypurinol in ischemic AKI, C57BL/6 male mice were intraperitoneally injected with oxypurinol and subjected to renal I/R or sham surgery. We found that oxypurinol-treated mice had lower plasma creatinine and blood urea nitrogen levels and tubular damage (hematoxylin-and-eosin staining) compared to vehicle-treated mice after renal I/R injury. Furthermore, oxypurinol treatment reduced kidney inflammation (i.e., neutrophil infiltration and MIP-2 mRNA induction), oxidative stress (i.e., 4-HNE, heme oxygenase-1 [HO-1], 8-OHdG expression, and Catalase mRNA induction), and apoptosis (i.e., TUNEL or cleaved caspase-3-positive renal tubular cells), compared to vehicle-treated mice. Mechanistically, oxypurinol induced protein expressions of HO-1, which is a critical cytoprotective enzyme during ischemic AKI, and oxypurinol-mediated protection against ischemic AKI was completely eliminated by pretreatment with tin protoporphyrin IX, an HO-1 inhibitor. In conclusion, oxypurinol protects against renal I/R injury by reducing oxidative stress, inflammation, and apoptosis via HO-1 induction, suggesting its preventive potential in ischemic AKI.

9.
Br J Clin Pharmacol ; 89(7): 1956-1964, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36036094

RESUMEN

AIMS: This study aimed to develop and evaluate an allopurinol adherence tool based on steady-state oxypurinol plasma concentrations, allopurinol's active metabolite. METHODS: Plasma oxypurinol concentrations were simulated stochastically from an oxypurinol pharmacokinetic model for allopurinol doses of 100-800 mg daily, accounting for differences in renal function, diuretic use and ethnicity. For each scenario, the 20th percentile for peak and trough concentrations defined the adherence threshold, below which imperfect adherence was assumed. Predictive performance was evaluated using both simulated low adherence and against data from 146 individuals with paired oxypurinol plasma concentrations and adherence measures. Sensitivity and specificity (S&S), negative and positive predictive values (NPV, PPV) and receiver operating characteristic (ROC) area under the curve (AUC) were determined. The predictive performance of the tool was evaluated using adherence data from an external study (CKD-FIX). RESULTS: The allopurinol adherence tool produced S&S values for trough thresholds of 89-98% and 76-84%, respectively, and 90%-98% and 76-83% for peak thresholds. PPV and NPV were 79-84% and 88-94%, respectively, for trough and 80-85% and 89-98%, respectively, for peak concentrations. The ROC AUC values ranged from 0.84 to 0.88 and from 0.86 to 0.89 for trough and peak concentrations, respectively. S&S values for the external evaluation were found to be 75.8% and 86.5%, respectively, producing an ROC AUC of 0.8113. CONCLUSION: A tool to identify people with gout who require additional support to maintain adherence using plasma oxypurinol concentrations was developed and evaluated. The predictive performance of the tool is suitable for adherence screening in clinical trials and may have utility in some clinical practice settings.


Asunto(s)
Gota , Comportamiento del Uso de la Herramienta , Humanos , Alopurinol/farmacocinética , Oxipurinol , Supresores de la Gota/farmacocinética , Gota/tratamiento farmacológico
10.
J Pharm Health Care Sci ; 8(1): 31, 2022 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-36476607

RESUMEN

BACKGROUND: Allopurinol is used to treat hyperuricemia and gout. It is metabolized to oxypurinol by xanthine oxidase (XO), and aldehyde oxidase (AO). Allopurinol and oxypurinol are potent XO inhibitors that reduce the plasma uric acid levels. Although oxypurinol levels show large inter-individual variations, high concentrations of oxypurinol can cause various adverse effects. Therefore, it is important to understand allopurinol metabolism by XO and AO. In this study we aimed to estimate the role of AO and XO in allopurinol metabolism by pre-administering Crl:CD and Jcl:SD rats, which have known strain differences in AO activity, with XO inhibitor febuxostat. METHODS: Allopurinol (30 or 100 mg/kg) was administered to Crl:CD and Jcl:SD rats with low and high AO activity, respectively, after pretreatment with or without febuxostat. The serum concentrations of allopurinol and oxypurinol were measured, and the area under the concentration-time curve (AUC) was calculated from the 48 h serum concentration-time profile. In vivo metabolic activity was measured as the ratio AUCoxypurinol /AUCallopurinol. RESULTS: Although no strain-specific differences were observed in the AUCoxypurinol/AUCallopurinol ratio in the allopurinol (30 mg/kg)-treated group, the ratio in Jcl:SD rats was higher than that in Crl:CD rats after febuxostat pretreatment. Contrastingly, the AUC ratio of allopurinol (100 mg/kg) was approximately 2-fold higher in Jcl:SD rats than that in Crl:CD rats. These findings showed that Jcl:SD rats had higher intrinsic AO activity than Crl:CD rats did. However, febuxostat pretreatment substantially decreased the activity, as measured by the AUC ratio using allopurinol (100 mg/kg), to 46 and 63% in Crl:CD rats and Jcl:SD rats, respectively, compared to the control group without febuxostat pretreatment. CONCLUSIONS: We elucidated the role of XO and AO in allopurinol metabolism in Crl:CD and Jcl:SD rats. Notably, AO can exert a proportionately greater impact on allopurinol metabolism at high allopurinol concentrations. AO's impact on allopurinol metabolism is meaningful enough that individual differences in AO may explain allopurinol toxicity events. Considering the inter-individual differences in AO activity, these findings can aid to dose adjustment of allopurinol to avoid potential adverse effects.

11.
Drug Test Anal ; 14(8): 1519-1524, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35355431

RESUMEN

The increasing global prevalence of gout and diabetes has led to a rise in the use of their respective medications, allopurinol and metformin. These are excreted via urine as oxypurinol and metformin and are discharged into wastewater and the environment. Current environmental monitoring of those two polar chemicals requires labour intensive and potentially inefficient sample pre-treatments, such as using solid-phase extraction or freeze-drying. This study validated a sensitive and simple method using direct-injection LC-MS/MS for the simultaneous measurement of oxypurinol and metformin in wastewater. The final method utilised a hydrophilic interaction liquid chromatography together with simple filtration through 0.2 µm regenerated cellulose filter followed by dilution in acetonitrile with a dilution factor of 10. The developed method was validated with the limit of quantifications (LOQ) of 0.11 and 0.34 µg/L for metformin and oxypurinol, respectively. The new method was applied to 42 influent wastewater samples and 6 effluent samples collected from 6 Australian wastewater treatment plants. Both compounds were detected well above the LOQ at concentrations 29-214 µg/L in influent and 2-53 µg/L in effluent for metformin, and 24-248 µg/L in influent and 4-81 µg/L in effluent for oxypurinol, demonstrating its high applicability.


Asunto(s)
Metformina , Contaminantes Químicos del Agua , Australia , Cromatografía Liquida/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Oxipurinol/análisis , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodos , Aguas Residuales/análisis , Contaminantes Químicos del Agua/análisis
12.
J Sep Sci ; 44(7): 1461-1470, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33527723

RESUMEN

A combination of allopurinol and benzbromarone is a common gout treatment protocol. A suboptimal response to allopurinol in patients is very common due to its pharmacokinetics variability. Moreover, the safe doses of benzbromarone is very crucial in patients with hepatic diseases. This raised the inquisitiveness to develop and optimize a capillary zone electrophoresis method for the determination of allopurinol and benzbromarone in their coformulation and in the presence of oxypurinol, the active metabolite of allopurinol, in biological and pharmaceutical matrices. The method greenness profile was assessed using green metric tools the "National Environmental Method Index," the "Analytical Eco-Scale," and the "Green Analytical Procedure Index" by which the method proved to be ecofriendly. The method was successfully applied for the analysis of the pharmaceutical preparation and urine samples spiked with both drugs and the active metabolite. The linearity range was 25.0-250.0 µg/mL for benzbromarone, 50.0-350.0 µg/mL for allopurinol, and 100.0-500.0 µg/mL for oxypurinol. The recoveries were 99.60 ± 0.67, 99.89 ± 0.98, and 98.71 ± 1.18% for benzbromarone, allopurinol, and oxypurinol, respectively. The analysis results indicate potential usefulness of capillary zone electrophoresis as a competitive and greener method of analysis in biological and quality control labs.


Asunto(s)
Alopurinol/análisis , Benzbromarona/análisis , Alopurinol/metabolismo , Benzbromarona/metabolismo , Electroforesis Capilar , Concentración de Iones de Hidrógeno , Estructura Molecular , Control de Calidad
13.
Curr Pharm Des ; 26(35): 4515-4521, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32787748

RESUMEN

BACKGROUND: COVID-19, caused by SARS-CoV-2, is a potentially lethal, rapidly-expanding pandemic and many efforts are being carried out worldwide to understand and control the disease. COVID-19 patients may display a cytokine release syndrome, which causes severe lung inflammation, leading, in many instances, to death. OBJECTIVE: This paper is intended to explore the possibilities of controlling the COVID-19-associated hyperinflammation by using licensed drugs with anti-inflammatory effects. HYPOTHESIS: We have previously described that pentoxifylline alone, or in combination with oxypurinol, reduces the systemic inflammation caused by experimentally-induced pancreatitis in rats. Pentoxifylline is an inhibitor of TNF-α production and oxypurinol inhibits xanthine oxidase. TNF-α, in turn, activates other inflammatory genes such as Nos2, Icam or IL-6, which regulate migration and infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the lung parenchyma. In acute pancreatitis, the anti-inflammatory action of pentoxifylline seems to be mediated by the prevention of the rapid and presumably transient loss of PP2A activity. This may also occur in the hyperinflammatory -cytokine releasing phase- of SARS-CoV-2 infection. Therefore, it may be hypothesized that early treatment of COVID-19 patients with pentoxifylline, alone or in combination with oxypurinol, would prevent the potentially lethal acute respiratory distress syndrome. CONCLUSION: Pentoxifylline and oxypurinol are licensed drugs used for diseases other than COVID-19 and, therefore, phase I clinical trials would not be necessary for the administration to SARS-CoV-2- infected people. It would be worth investigating their potential effects against the hyperinflammatory response to SARS-CoV-2 infection.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/prevención & control , Oxipurinol/uso terapéutico , Pentoxifilina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Enfermedad Aguda , Animales , Betacoronavirus , COVID-19 , Síndrome de Liberación de Citoquinas/virología , Humanos , Pancreatitis , Pandemias , Ratas , SARS-CoV-2
14.
Sci Total Environ ; 715: 136925, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32007890

RESUMEN

Allopurinol, a first-line gout treatment drug in Australia, was assessed as a wastewater-based epidemiology biomarker of gout via quantification of the urinary metabolite, oxypurinol in wastewater. The in-sewer stability of oxypurinol was examined using laboratory-scale sewer reactors. Wastewater from 75 wastewater treatment plants across Australia, covering approximately 52% (12.2 million) of the country's population, was collected on the 2016 census day. Oxypurinol was quantified in the wastewater samples and population-weighted mass loads calculated. Pearson and Spearman rank-order correlations were applied to investigate any link between allopurinol, other selected wastewater biomarkers, and socio-economic indicators. Oxypurinol was shown to be stable in sewer conditions and suitable as a WBE biomarker. Oxypurinol was detected in all wastewater samples. The estimated consumption of allopurinol ranged from 1.9 to 32 g/day/1000 people equating to 4.8 to 80 DDD/day/1000 people. The prevalence of gout across all tested sewer catchments was between 0.5% to 8%, with a median of 2.9% nationally. No significant positive correlation was observed between allopurinol consumption and alcohol consumption, mean age of catchment population, remoteness or higher socioeconomic status. There was a significant positive correlation with selective analgesic drug use. Wastewater analysis can be used to study gout prevalence and can provide additional insights on population level risk factors when triangulated with other biomarkers.


Asunto(s)
Gota , Australia , Oxipurinol , Prevalencia , Aguas Residuales
15.
Front Neurol ; 10: 447, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31118919

RESUMEN

Background: Asphyxia is the most common cause of brain damage in newborns. Substantial evidence indicates that leukocyte recruitment in the cerebral vasculature during asphyxia contributes to this damage. We tested the hypothesis that superoxide radical ( O 2 ⋅ _ ) promotes an acute post-asphyxial inflammatory response and blood-brain barrier (BBB) breakdown. We investigated the effects of removing O 2 ⋅ _ by superoxide dismutase (SOD) or C3, the cell-permeable SOD mimetic, in protecting against asphyxia-related leukocyte recruitment. We also tested the hypothesis that xanthine oxidase activity is one source of this radical. Methods: Anesthetized piglets were tracheostomized, ventilated, and equipped with closed cranial windows for the assessment of post-asphyxial rhodamine 6G-labeled leukocyte-endothelial adherence and microvascular permeability to sodium fluorescein in cortical venules. Asphyxia was induced by discontinuing ventilation. SOD and C3 were administered by cortical superfusion. The xanthine oxidase inhibitor oxypurinol was administered intravenously. Results: Leukocyte-venular adherence significantly increased during the initial 2 h of post-asphyxial reperfusion. BBB permeability was also elevated relative to non-asphyxial controls. Inhibition of O 2 ⋅ _ production by oxypurinol, or elimination of O 2 ⋅ _ by SOD or C3, significantly reduced rhodamine 6G-labeled leukocyte-endothelial adherence and improved BBB integrity, as measured by sodium fluorescein leak from cerebral microvessels. Conclusion: Using three different strategies to either prevent formation or enhance elimination of O 2 ⋅ _ during the post-asphyxial period, we saw both reduced leukocyte adherence and preserved BBB function with treatment. These findings suggest that agents which lower O 2 ⋅ _ in brain may be attractive new therapeutic interventions for the protection of the neonatal brain following asphyxia.

16.
Physiol Rep ; 6(5)2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29488355

RESUMEN

To provide insight into pharmacological treatment of hyperuricemia we developed a semi-mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR, FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Co-administration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure-response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations.


Asunto(s)
Hiperuricemia/tratamiento farmacológico , Modelos Teóricos , Medicina de Precisión/métodos , Alopurinol/administración & dosificación , Alopurinol/uso terapéutico , Ensayos Clínicos como Asunto , Febuxostat/administración & dosificación , Febuxostat/uso terapéutico , Humanos , Hiperuricemia/metabolismo , Hiperuricemia/fisiopatología , Tioglicolatos/administración & dosificación , Tioglicolatos/uso terapéutico , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Ácido Úrico/metabolismo , Uricosúricos/administración & dosificación , Uricosúricos/uso terapéutico
17.
Drug Metab Pharmacokinet ; 33(1): 77-81, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29342419

RESUMEN

Hyperuricemia induces gout and kidney stones and accelerates the progression of renal and cardiovascular diseases. Adenosine 5'-triphosphate-binding cassette subfamily G member 2 (ABCG2) is a urate transporter, and common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and semi-functional Q141K (rs2231142), are risk factors for hyperuricemia and gout. A recent genome wide association study suggested that allopurinol, a serum uric acid-lowering drug that inhibits xanthine dehydrogenase, is a potent substrate of ABCG2. In this study, we aimed to examine the transport of xanthine dehydrogenase inhibitors via ABCG2. Our results show that ABCG2 transports oxypurinol, an active metabolite of allopurinol, whereas allopurinol and febuxostat, a new xanthine dehydrogenase inhibitor, are not substrates of ABCG2. The amount of oxypurinol transported by ABCG2 vesicles significantly increased in the presence of ATP, compared to that observed with mock vesicles. Since the half-life of oxypurinol is longer than that of allopurinol, the xanthine dehydrogenase-inhibiting effect of allopurinol mainly depends on its metabolite, oxypurinol. Our results indicate that the serum level of oxypurinol would increase in patients with ABCG2 dysfunction.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Alopurinol/metabolismo , Proteínas de Neoplasias/metabolismo , Oxipurinol/metabolismo , Xantina Deshidrogenasa/antagonistas & inhibidores , Xantina Deshidrogenasa/metabolismo , Transporte Biológico/fisiología , Membrana Celular/metabolismo , Inhibidores Enzimáticos/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Hiperuricemia/metabolismo
18.
Anal Bioanal Chem ; 409(30): 7097-7103, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29018901

RESUMEN

A method has been developed for the trace analysis of oxypurinol that is considered as an active pharmaceutical ingredient and an emerging environmental contaminant. The method achieved the identification and quantification of oxypurinol in surface water samples utilizing solid phase extraction and ultra high-performance liquid chromatography with diode array and fluorescence detection for the first time. Four principal parameters of solid phase extraction were optimized to obtain maximum extraction efficiency. Under the isocratic elution of methanol/water (5:95, v/v) and the excitation/emission wavelength of 254/359 nm, a rapid determination was achieved in 2.0 min with good linearity of 1.05-351 µg/L (coefficient of determination above 0.9998). The limit of detection and method detection limit were 0.210 µg/L and 1.34 ng/L, respectively. Precision of the method was evaluated and a relative standard deviation value of 3.3% was obtained for analyses of six replicate spiking blank samples (200 mL, 176 ng/L) according to the overall proposed procedure. The method showed a great anti-interference ability and average spiked recoveries of oxypurinol in five surface water samples were in the range of 94.5-111%. The ability of the method to detect and correctly identify oxypurinol can significantly promote investigation on the occurrence of oxypurinol in water and its potential (eco-)toxicological effects. Graphical abstract Quantification of the emerging contaminant oxypurinol in s urface water using SPE/UHPLC-FLD.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Oxipurinol/química , Extracción en Fase Sólida/métodos , Contaminantes Químicos del Agua/análisis , Fluorescencia , Límite de Detección , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem/métodos , Agua/química
19.
Br J Clin Pharmacol ; 83(9): 2015-2026, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28417592

RESUMEN

AIMS: The aims of the study were to: 1) determine if a plasma oxypurinol concentration-response relationship or an allopurinol dose-response relationship best predicts the dose requirements of allopurinol in the treatment of gout; and 2) to construct a nomogram for calculating the optimum maintenance dose of allopurinol to achieve target serum urate (SU) concentrations. METHODS: A nonlinear regression analysis was used to examine the plasma oxypurinol concentration- and allopurinol dose-response relationships with serum urate. In 81 patients (205 samples), creatinine clearance (CLCR ), concomitant diuretic use and SU concentrations before (UP ) and during (UT ) treatment were monitored across a range of allopurinol doses (D, 50-700 mg daily). Plasma concentrations of oxypurinol (C) were measured in 47 patients (98 samples). Models (n = 47 patients) and predictions from each relationship were compared using F-tests, r2 values and paired t-tests. The best model was used to construct a nomogram. RESULTS: The final plasma oxypurinol concentration-response relationship (UT = UP - C*(UP - UR )/(ID50 + C), r2  = 0.64) and allopurinol dose-response relationship (UT = UP - D* (UP - UR )/(ID50 + D), r2  = 0.60) did not include CLCR or diuretic use as covariates. There was no difference (P = 0.87) between the predicted SU concentrations derived from the oxypurinol concentration- and allopurinol dose-response relationships. The nomogram constructed using the allopurinol dose-response relationship for all recruited patients (n = 81 patients) required pretreatment SU as the predictor of allopurinol maintenance dose. CONCLUSIONS: Plasma oxypurinol concentrations, CLCR and diuretic status are not required to predict the maintenance dose of allopurinol. Using the nomogram, the maintenance dose of allopurinol estimated to reach target concentrations can be predicted from UP .


Asunto(s)
Alopurinol/farmacología , Cálculo de Dosificación de Drogas , Gota/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alopurinol/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Supresores de la Gota/farmacocinética , Supresores de la Gota/farmacología , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Oxipurinol/sangre , Ácido Úrico/sangre , Adulto Joven
20.
Eur J Clin Pharmacol ; 73(1): 71-78, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27683090

RESUMEN

PURPOSE: The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients. METHODS: Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were used to develop a population pharmacokinetic model in NONMEM. Deterministic simulations were used to predict the steady-state area under the oxypurinol plasma concentration time curve over 1 week (AUC7days). RESULTS: The pharmacokinetics of oxypurinol were best described by a one-compartment model with a separate parameter for dialytic clearance. Allopurinol 100 mg daily produced an AUC7days of 279 µmol/L h in dialysis patients, a value 50-75 % lower than the AUC7days predicted for patients with normal renal function taking 200 to 400 mg daily (427-855 µmol/L h). Dosing pre-dialysis resulted in about a 25-35 % reduction in exposure compared to post-dialysis. CONCLUSIONS: Oxypurinol is efficiently removed by dialysis. The population dialytic and total (non-dialytic) clearance of oxypurinol were found to be 8.23 and 1.23 L/h, standardised to a fat-free mass of 70 kg and creatinine clearance of 6 L/h, respectively. Our results suggest that if the combination of low-dose allopurinol and haemodialysis does not result in sustained urate lowering below treatment targets (serum urate ≤0.36 mmol/L), then allopurinol doses may be increased to optimise oxypurinol exposure.


Asunto(s)
Alopurinol/farmacocinética , Supresores de la Gota/farmacocinética , Modelos Biológicos , Oxipurinol/sangre , Diálisis Renal , Adulto , Anciano , Anciano de 80 o más Años , Alopurinol/sangre , Femenino , Gota/sangre , Gota/tratamiento farmacológico , Gota/metabolismo , Supresores de la Gota/sangre , Humanos , Masculino , Persona de Mediana Edad
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