RESUMEN
AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.
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Alopurinol , Relación Dosis-Respuesta a Droga , Supresores de la Gota , Gota , Modelos Biológicos , Ácido Úrico , Alopurinol/administración & dosificación , Alopurinol/farmacocinética , Humanos , Gota/tratamiento farmacológico , Gota/sangre , Supresores de la Gota/administración & dosificación , Supresores de la Gota/farmacocinética , Ácido Úrico/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Cálculo de Dosificación de Drogas , Simulación por ComputadorRESUMEN
AIMS: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). METHODS: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. RESULTS: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). CONCLUSIONS: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.
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Alopurinol , Febuxostat , Supresores de la Gota , Gota , Cumplimiento de la Medicación , Autoinforme , Ácido Úrico , Humanos , Gota/tratamiento farmacológico , Gota/sangre , Alopurinol/administración & dosificación , Alopurinol/uso terapéutico , Supresores de la Gota/administración & dosificación , Supresores de la Gota/uso terapéutico , Cumplimiento de la Medicación/estadística & datos numéricos , Australia , Masculino , Femenino , Persona de Mediana Edad , Febuxostat/administración & dosificación , Febuxostat/uso terapéutico , Autoinforme/estadística & datos numéricos , Ácido Úrico/sangre , Anciano , Adulto , Bases de Datos FactualesRESUMEN
Gout is a metabolic condition characterized by the accumulation of urate crystals in the synovial joints. These crystal depositions result in joint swelling and increased concentration of serum uric acid in blood. The commercially available drugs lower serum uric acid levels and reduce inflammation, but these standard therapies have many side effects. This study aimed to investigate anti-gout and anti-inflammatory properties of curcumin nanoparticles (CNPs). For this purpose, CNPs were prepared by dissolving curcumin into dichloromethane. Then, gout was induced by injecting monosodium urate crystals (MSU) in the ankle joint and in the intra-peritoneal cavity which caused ankle swelling and increased blood uric acid levels. CNPs in different concentrations (5, 10, and 20 ppm) and allopurinol were orally administered. The MSU crystals increased the xanthine oxidase levels both in serum and the liver. Moreover, MSU crystals increased the serum levels of interleukin 1ß, interleukin-6, tumor necrosis factor-alpha, liver function tests markers, renal function tests markers, and lipid profiles. However, the administration of CNPs decreased the levels of all these variables. CNPs increased the serum high-density lipoprotein and interleukin-10 levels. Moreover, CNPs also reduced ankle swelling significantly. Hence, the levels of xanthine oxidase, uric acid and ankle swelling were reduced significantly by oral administration of CNPs. Our findings indicate that CNPs through their anti-inflammatory properties significantly alleviate gouty arthritis. Thus, the study concluded that CNPs can be developed as an efficient anti-gout agent with minimal side effects.
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Antiinflamatorios , Artritis Gotosa , Curcumina , Ratones Endogámicos BALB C , Nanopartículas , Ácido Úrico , Animales , Curcumina/farmacología , Curcumina/administración & dosificación , Ácido Úrico/sangre , Artritis Gotosa/tratamiento farmacológico , Artritis Gotosa/inducido químicamente , Ratones , Nanopartículas/administración & dosificación , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Masculino , Xantina Oxidasa/metabolismo , Supresores de la Gota/farmacología , Supresores de la Gota/administración & dosificación , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamenteRESUMEN
INTRODUCTION: To this date, a causal relationship between febuxostat and cardiovascular disease remains controversial as comparison between trials can be challenging and may lead to misleading conclusions, especially when facing heterogeneous cardiovascular outcomes. We aimed to compare the cardiovascular outcomes in the most pertinent trials of febuxostat compared with controls. METHODS: We searched electronic databases using a PICOS-style approach search strategy of randomized controlled trials (RCTs) on cardiovascular outcomes of febuxostat in patients with gout or hyperuricemia. We conducted a quality and risk of bias assessment of the included clinical trials. The definition of major adverse cardiovascular event as well as all reported cardiovascular outcomes were retrieved from every involved trial. RESULTS: Of the 1173 records identified from all sources, 20 RCTs were included in the analysis. The mean duration of follow-up was 69.7 ± 81.5 weeks, and febuxostat dose ranged from 10 to 240 mg with 80 mg being the most commonly used dosage. Overall, the quality of evidence deriving from all RCTs showed concerns in most studies (65%). Major adverse cardiovascular event was defined in 7 of the 20 RCTs (35%), and cardiovascular outcome reporting was very heterogeneous. Overall, the data of cardiovascular safety of febuxostat were reassuring. CONCLUSIONS: Our systematic review showed high level of concerns in quality assessment domains as well heterogeneous cardiovascular outcomes across included studies. Cardiovascular outcomes in the majority of White males with gout treated with febuxostat were reassuring when compared with allopurinol. Further studies are needed to draw conclusions in patients with severe cardiovascular disease.
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Enfermedades Cardiovasculares , Febuxostat , Supresores de la Gota , Gota , Hiperuricemia , Ensayos Clínicos Controlados Aleatorios como Asunto , Febuxostat/uso terapéutico , Febuxostat/efectos adversos , Febuxostat/administración & dosificación , Humanos , Gota/tratamiento farmacológico , Hiperuricemia/tratamiento farmacológico , Supresores de la Gota/efectos adversos , Supresores de la Gota/administración & dosificación , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & controlRESUMEN
OBJECTIVES: Currently, gout management, particularly urate-lowering therapy (ULT), is often suboptimal. Nurses successfully manage various diseases including gout. As gout prevalence is rising, and rheumatologists and general practitioners face shortages, a new approach is imperative. This real-life prospective cohort study evaluated the effectiveness of nurse-led care employing a treat-to-target strategy for gout management over a 2-year period. METHODS: All consecutively confirmed gout patients were included. The nurse-led clinic provided a structured treatment plan with consultations, patient leaflets, telephone contacts and laboratory monitoring. After a year of nurse-led care, patients transitioned to continued care in general practice. Follow-up data were complete through registries. The primary outcome was achieving target p-urate levels (<0.36 mmol/L) at 2 years after diagnosis. Secondary outcomes included treatment continuation and achievement of target p-urate levels in specific subgroups. The results were compared with patients diagnosed in the same clinic but followed up in 'usual care'. RESULTS: In the nurse-led group (n=114), 83% achieved target p-urate levels and ULT was continued by 98%. This trend persisted across various patient subgroups. Only 44% of patients in usual care achieved target p-urate and with insufficient doses of allopurinol . Nurse-led care involved an average of two visits and three telephone contacts over 336 days. The 2-year mortality rate was 15%. CONCLUSIONS: Nurse-led gout care, employing a targeted approach, was associated with a very high uptake of and adherence to ULT. The encouraging results were not achieved in usual care although a direct comparison might be influenced by selection bias.
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Supresores de la Gota , Gota , Ácido Úrico , Humanos , Gota/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Ácido Úrico/sangre , Estudios Prospectivos , Supresores de la Gota/uso terapéutico , Supresores de la Gota/administración & dosificación , Resultado del Tratamiento , Pautas de la Práctica en Enfermería , Alopurinol/uso terapéutico , Manejo de la EnfermedadRESUMEN
INTRODUCTION: Gout is one of the most common forms of arthritis worldwide. Gout is particularly prevalent in Aotearoa/New Zealand and is estimated to affect 13.1% of Maori men, 22.9% of Pacific men and 7.4% of New Zealand European men. Effective long-term treatment requires lowering serum urate to <0.36 mmol/L. Allopurinol is the most commonly used urate-lowering medication worldwide. Despite its efficacy and safety, the allopurinol dose escalation treat-to-target serum urate strategy is difficult to implement and there are important inequities in allopurinol prescribing in Aotearoa. The escalation strategy is labour intensive, time consuming and costly for people with gout and the healthcare system. An easy and effective way to dose-escalate allopurinol is required, especially as gout disproportionately affects working-age Maori men and Pacific men, who frequently do not receive optimal care. METHODS AND ANALYSIS: A 12-month non-inferiority randomised controlled trial in people with gout who have a serum urate ≥ 0.36 mmol/l will be undertaken. 380 participants recruited from primary and secondary care will be randomised to one of the two allopurinol dosing strategies: intensive nurse-led treat-to-target serum urate dosing (intensive treat-to-target) or protocol-driven dose escalation based on dose predicted by an allopurinol dosing model (Easy-Allo). The primary endpoint will be the proportion of participants who achieve target serum urate (<0.36 mmol/L) at 12 months. ETHICS AND DISSEMINATION: The New Zealand Northern B Health and Disability Ethics Committee approved the study (2022 FULL 13478). Results will be disseminated in peer-reviewed journals and to participants. TRIAL REGISTRATION NUMBER: ACTRN12622001279718p.
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Alopurinol , Supresores de la Gota , Gota , Ácido Úrico , Humanos , Alopurinol/administración & dosificación , Alopurinol/uso terapéutico , Gota/tratamiento farmacológico , Gota/sangre , Nueva Zelanda , Supresores de la Gota/administración & dosificación , Supresores de la Gota/uso terapéutico , Ácido Úrico/sangre , Masculino , Relación Dosis-Respuesta a Droga , Adulto , Estudios de Equivalencia como Asunto , FemeninoRESUMEN
INTRODUCTION: The aim of the study was to explore the association between urate-lowering agents and reduced response to erythropoietin-stimulating agents in patients suffering from chronic kidney disease G5. METHODS: We conducted a cross-sectional, multicenter study in Japan between April and June 2013, enrolling patients aged 20 years or older with an estimated glomerular filtration rate of ≤15 mL/min/1.73 m2. Exclusion criteria encompassed patients with a history of hemodialysis, peritoneal dialysis, or organ transplantation. The patients were categorized into four groups based on the use of urate-lowering drugs: high-dose allopurinol (>50 mg/day), low-dose allopurinol (≤50 mg/day), febuxostat, and no-treatment groups. We used a multivariable logistic regression model, adjusted for covariates, to determine the odds ratio (OR) for erythropoietin hyporesponsiveness, defined by an erythropoietin resistance index (ERI) of ≥10, associated with urate-lowering drugs. RESULTS: A total of 542 patients were included in the analysis, with 105, 36, 165, and 236 patients in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The median and quartiles of ERIs were 6.3 (0, 12.2), 3.8 (0, 11.2), 3.4 (0, 9.8), and 4.8 (0, 11.2) in the high-dose allopurinol, low-dose allopurinol, febuxostat, and no-treatment groups, respectively. The multivariate regression model showed a statistically significant association between the high-dose allopurinol group and erythropoietin hyporesponsiveness, compared to the no-treatment group (OR = 1.98, 95% confidence interval: 1.10-3.57). CONCLUSIONS: Our study suggests that the use of high-dose allopurinol exceeding the optimal dose may lead to hyporesponsiveness to erythropoiesis-stimulating agents.
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Alopurinol , Eritropoyetina , Insuficiencia Renal Crónica , Humanos , Masculino , Femenino , Alopurinol/administración & dosificación , Alopurinol/uso terapéutico , Persona de Mediana Edad , Anciano , Estudios Transversales , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Eritropoyetina/administración & dosificación , Supresores de la Gota/administración & dosificación , Supresores de la Gota/uso terapéutico , Adulto , Relación Dosis-Respuesta a Droga , Ácido Úrico/sangre , Hematínicos/administración & dosificación , Hematínicos/uso terapéutico , Japón , Febuxostat/administración & dosificación , Febuxostat/uso terapéuticoRESUMEN
OBJECTIVE: We systematically examined comparative gout flare risk after initiation or escalation of different urate-lowering therapies (ULTs), comparative flare risk with and without concomitant flare prophylaxis, adverse event rates associated with flare prophylaxis, and optimal duration of flare prophylaxis. METHODS: We searched the Medline, Embase, Web of Science, and Cochrane databases and clinical trial registries from inception to November 2021 for trials investigating adults with gout initiating or escalating ULT. We performed random effects network meta-analyses and calculated risk ratios (RRs) between treatments. Bias was assessed using the revised Cochrane risk-of-bias tool. RESULTS: We identified 3,775 records, of which 29 publications (27 trials) were included. When compared to placebo plus prophylaxis, the RR of flares ranged from 1.08 (95% confidence interval [CI] 0.87-1.33) for febuxostat 40 mg plus prophylaxis to RR 2.65 [95% CI 1.58-4.45] for febuxostat 80 mg plus lesinurad 400 mg plus prophylaxis. Compared to ULT alone, the RR of flares was lower for ULT plus rilonacept 160 mg (RR 0.35 [95% CI 0.25-0.50]), ULT plus rilonacept 80 mg (RR 0.43 [95% CI 0.31-0.60]) and ULT plus colchicine (RR 0.50 [95% CI 0.35-0.72]). There was limited evidence for other flare prophylaxis and on prophylaxis harms and optimal duration. Primarily because of missing outcome data and bias in the selection of reported results, 71.4% and 63.4% of studies were assessed as high risk of bias for flares and adverse events, respectively. CONCLUSION: The RR of flares when introducing ULT varies depending on ULT drug and dosing strategies. There were limited data on ULT escalation. Flare prophylaxis with colchicine and rilonacept reduces flare incidence. More research is required on the harms and optimal duration of prophylaxis.
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Supresores de la Gota , Gota , Metaanálisis en Red , Brote de los Síntomas , Ácido Úrico , Humanos , Gota/tratamiento farmacológico , Gota/sangre , Supresores de la Gota/uso terapéutico , Supresores de la Gota/efectos adversos , Supresores de la Gota/administración & dosificación , Ácido Úrico/sangre , Medición de Riesgo , Colchicina/uso terapéutico , Colchicina/efectos adversos , Colchicina/administración & dosificación , Febuxostat/uso terapéutico , Febuxostat/administración & dosificación , Febuxostat/efectos adversos , Resultado del Tratamiento , Factores de Riesgo , Quimioterapia Combinada , Proteínas Recombinantes de FusiónAsunto(s)
Alopurinol , Supresores de la Gota , Gota , Humanos , Alopurinol/uso terapéutico , Alopurinol/administración & dosificación , Gota/tratamiento farmacológico , Gota/complicaciones , Supresores de la Gota/administración & dosificación , Supresores de la Gota/uso terapéutico , Masculino , Manía/tratamiento farmacológico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/complicaciones , Persona de Mediana EdadRESUMEN
The aim of this study was to observe the effects of uric acid lowering therapy (UALT), febuxostat and allopurinol, on blood pressure (BP) and serum creatinine level. Post-hoc data were derived from a phase-III, randomised, double-blind, 4-week trial of male gouty patients that compared the safety and efficacy of febuxostat and allopurinol in adults with gout. The subjects were randomly assigned to one of five groups, 35-37 in each group (febuxostat: 40, 80, 120 mg/d; allopurinol: 300 mg/d; control group: placebo). Blood pressure and serum creatinine level were measured at baseline and at weeks 2 and 4. Diastolic BP and creatinine level had decreased significantly in the UALT groups compared to the control group at week 4. Diastolic BP had decreased significantly in the allopurinol group and serum creatinine level had decreased significantly in the febuxostat groups at week 4. After adjusting for confounding variables, serum uric acid changes were found to be significantly correlated with changes in serum creatinine level but were not associated with changes in systolic or diastolic BP. UALT in gouty subjects significantly decreased diastolic BP and serum creatinine level. Changes in uric acid were significantly correlated with those in serum creatinine level, suggesting the feasibility of renal function improvement through UALT in gouty men.