RESUMEN
Nonalcoholic steatohepatitis (NASH) is an inflammatory and fibrotic liver disease that has reached epidemic proportions and has no approved pharmacologic therapies. Research and drug development efforts are hampered by inadequate preclinical models. This research describes a three-dimensional bioprinted liver tissue model of NASH built using primary human hepatocytes and nonparenchymal liver cells (hepatic stellate cells, liver sinusoidal endothelial cells, and Kupffer cells) from either healthy or NASH donors. Three-dimensional tissues bioprinted with cells sourced from diseased patients showed a NASH phenotype, including fibrosis. More importantly, this NASH phenotype occurred without the addition of disease-inducing agents. Bioprinted tissues composed entirely of healthy cells exhibited significantly less evidence of disease. The role of individual cell types in driving the NASH phenotype was examined by producing chimeric bioprinted tissues composed of healthy cells together with the addition of one or more diseased nonparenchymal cell types. These experiments reveal a role for both hepatic stellate and liver sinusoidal endothelial cells in the disease process. This model represents a fully human system with potential to detect clinically active targets and eventually therapies.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Células Endoteliales/metabolismo , Hígado/metabolismo , Hepatocitos/metabolismo , Macrófagos del Hígado/metabolismo , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/patologíaRESUMEN
To improve the understanding of the complex biological process underlying the development of non-alcoholic steatohepatitis (NASH), 3D imaging flow cytometry (3D-IFC) with transmission and side-scattered images were used to characterize hepatic stellate cell (HSC) and liver endothelial cell (LEC) morphology at single-cell resolution. In this study, HSC and LEC were obtained from biopsy-proven NASH subjects with early-stage NASH (F2-F3) and healthy controls. Here, we applied single-cell imaging and 3D digital reconstructions of healthy and diseased cells to analyze a spatially resolved set of morphometric cellular and texture parameters that showed regression with disease progression. By developing a customized autoencoder convolutional neural network (CNN) based on label-free cell transmission and side scattering images obtained from a 3D imaging flow cytometer, we demonstrated key regulated cell types involved in the development of NASH and cell classification performance superior to conventional machine learning methods.
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Enfermedad del Hígado Graso no Alcohólico , Inteligencia Artificial , Citometría de Flujo , Humanos , Imagenología Tridimensional , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , PronósticoRESUMEN
OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Gota , Proteínas de Neoplasias/genética , Ácido Úrico/sangre , Adulto , Edad de Inicio , Europa (Continente)/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Gota/sangre , Gota/epidemiología , Gota/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Brote de los SíntomasAsunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Febuxostat/uso terapéutico , Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Gota/genética , Proteínas de Neoplasias/genética , Adulto , Anciano , Alelos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
Lesinurad [Zurampic; 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)], a selective inhibitor of uric acid reabsorption transporters approved for the treatment of gout, is a racemate of two atropisomers. The objective of this investigation was to evaluate the stereoselectivity of metabolism, the inhibitory potency on kidney uric acid reabsorption transporters (URAT1 and OAT4), and the clinical pharmacokinetics of the lesinurad atropisomers. Incubations with human liver microsomes (HLM), recombinant CYP2C9, and recombinant CYP3A4 were carried out to characterize the stereoselective formation of three metabolites: M3 (hydroxylation), M4 (a dihydrodiol metabolite), and M6 (S-dealkylation). The formation of M3 in HLM with atropisomer 1 was approximately twice as much as that with atropisomer 2, whereas formation of M4 with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy human volunteers, the systemic exposure (C max at steady state and area under the concentration-time curve from time zero to the time of dosing interval) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 stable cells expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.
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Transportadores de Anión Orgánico/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Reabsorción Renal/efectos de los fármacos , Tioglicolatos/farmacología , Triazoles/farmacología , Ácido Úrico/metabolismo , Uricosúricos/farmacología , Administración Oral , Adulto , Gota/tratamiento farmacológico , Células HEK293 , Voluntarios Sanos , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Microsomas Hepáticos , Persona de Mediana Edad , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Tioglicolatos/química , Tioglicolatos/metabolismo , Tioglicolatos/uso terapéutico , Triazoles/química , Triazoles/metabolismo , Triazoles/uso terapéutico , Ácido Úrico/sangre , Ácido Úrico/orina , Uricosúricos/química , Uricosúricos/metabolismo , Uricosúricos/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Ferritin positively associates with serum urate and an interventional study suggests that iron has a role in triggering gout flares. The objective of this study was to further explore the relationship between iron/ferritin and urate/gout. METHODS: European (100 cases, 60 controls) and Polynesian (100 cases, 60 controls) New Zealand (NZ) males and 189 US male cases and 60 male controls participated. The 10,727 participants without gout were from the Jackson Heart (JHS; African American = 1260) and NHANES III (European = 5112; African American = 4355) studies. Regression analyses were adjusted for age, sex, body mass index and C-reactive protein. To test for a causal relationship between ferritin and urate, bidirectional two-sample Mendelian randomization analysis was performed. RESULTS: Serum ferritin positively associated with gout in NZ Polynesian (OR (per 10 ng ml- 1 increase) = 1.03, p = 1.8E-03) and US (OR = 1.11, p = 7.4E-06) data sets but not in NZ European (OR = 1.00, p = 0.84) data sets. Ferritin positively associated with urate in NZ Polynesian (ß (mg dl- 1) = 0.014, p = 2.5E-04), JHS (ß = 0.009, p = 3.2E-05) and NHANES III (European ß = 0.007, p = 5.1E-11; African American ß = 0.011, p = 2.1E-16) data sets but not in NZ European (ß = 0.009, p = 0.31) or US (ß = 0.041, p = 0.15) gout data sets. Ferritin positively associated with the frequency of gout flares in two of the gout data sets. By Mendelian randomization analysis a one standard deviation unit increase in iron and ferritin was, respectively, associated with 0.11 (p = 8E-04) and 0.19 mg dl- 1 (p = 2E-04) increases in serum urate. There was no evidence for a causal effect of urate on iron/ferritin. CONCLUSIONS: These data replicate the association of ferritin with serum urate. Increased ferritin levels associated with gout and flare frequency. There was evidence of a causal effect of iron and ferritin on urate.
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Ferritinas/sangre , Gota/sangre , Ácido Úrico/sangre , Negro o Afroamericano , Femenino , Gota/etnología , Humanos , Masculino , Persona de Mediana Edad , Nativos de Hawái y Otras Islas del Pacífico , Nueva Zelanda , Encuestas Nutricionales , Población BlancaRESUMEN
PURPOSE: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of gout and asymptomatic hyperuricemia. This study evaluated verinurad pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and non-Asian adult male subjects. METHODS: This was a Phase I, randomized, single-blind, placebo-controlled study. Panels of 8 Japanese subjects were randomized to receive oral verinurad (2.5-15 mg) or placebo administered as a single dose in a fasted and fed state and as once-daily doses for 7 days in a fed state. Eight non-Asian subjects received verinurad 10 mg as a single dose (fasted and fed) and multiple doses in the fed state. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events and laboratory data. RESULTS: Of 48 randomized subjects, 46 (Japanese, 39; non-Asian, 7) completed the study. Following single or multiple doses in Japanese subjects, maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a near dose-proportional manner. Time to Cmax (Tmax) was ~1.25-2.0 hours with fasting. A moderate-fat meal delayed Tmax (range 3.0-5.0 hours) and had a variable effect on AUC (0%-97% increase) and Cmax (0%-26% increase) across the dose groups. Following multiple verinurad 10 mg doses, Cmax and AUC were 38% and 23% higher, respectively, in Japanese vs non-Asian subjects, largely due to body weight differences. Mean reduction of serum urate following multiple verinurad 10 mg doses was 46% and 44% after 24 hours in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses. CONCLUSION: Verinurad monotherapy lowered serum urate and was well tolerated in both healthy Japanese and non-Asian males, while small differences in plasma pharmacokinetics were observed. These data support further evaluation of once-daily verinurad as a treatment for gout and asymptomatic hyperuricemia.
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Pueblo Asiatico , Túbulos Renales/efectos de los fármacos , Naftalenos , Propionatos , Piridinas , Eliminación Renal/efectos de los fármacos , Reabsorción Renal/efectos de los fármacos , Ácido Úrico/metabolismo , Uricosúricos/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Esquema de Medicación , Semivida , Voluntarios Sanos , Humanos , Túbulos Renales/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , Naftalenos/administración & dosificación , Naftalenos/efectos adversos , Naftalenos/farmacocinética , Naftalenos/farmacología , Propionatos/administración & dosificación , Propionatos/efectos adversos , Propionatos/farmacocinética , Propionatos/farmacología , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacocinética , Piridinas/farmacología , Método Simple Ciego , Ácido Úrico/sangre , Ácido Úrico/orina , Uricosúricos/administración & dosificación , Uricosúricos/sangre , Adulto JovenRESUMEN
Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of hyperuricemia and gout. This phase 1b, multiple-dose, drug-drug interaction study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in combination with allopurinol. Adult males with gout were randomized to receive once-daily oral doses of allopurinol 300 mg or verinurad 10 mg alone for 7 days, allopurinol 300 mg + verinurad 10 mg on days 8 to 14, and the alternative single agent on days 15 to 21. Colchicine 0.6 mg was taken prophylactically for gout flares. Plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol (allopurinol active metabolite), colchicine (plasma only), and uric acid. Safety was assessed by adverse events (AEs) and laboratory tests. Verinurad plasma exposure was unaffected by allopurinol. Verinurad increased the maximum observed plasma concentration (Cmax ) for allopurinol by 33%; the area under the plasma concentration-time curve (AUC) was unaffected. Oxypurinol Cmax and AUC were reduced 32% and 38%, respectively, by verinurad. Colchicine plasma exposure was unaltered by verinurad. The maximum decrease in serum urate was greater with verinurad + allopurinol (65%) than with verinurad (51%) or allopurinol (43%) alone. Compared with the baseline rate, the maximum rate of uric acid excreted in urine was +56% with verinurad, -46% with allopurinol, and unchanged with verinurad + allopurinol. No serious AEs, discontinuations due to AEs, or clinically significant laboratory abnormalities were noted. Despite decreased systemic exposure of allopurinol and oxypurinol in the presence of verinurad, the combination resulted in greater serum urate reduction compared with either drug alone and was well tolerated at the studied doses.
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Supresores de la Gota/farmacocinética , Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Naftalenos/farmacocinética , Naftalenos/uso terapéutico , Propionatos/farmacocinética , Propionatos/uso terapéutico , Piridinas/farmacocinética , Piridinas/uso terapéutico , Adolescente , Adulto , Anciano , Alopurinol/metabolismo , Alopurinol/farmacocinética , Alopurinol/uso terapéutico , Área Bajo la Curva , Esquema de Medicación , Supresores de la Gota/administración & dosificación , Supresores de la Gota/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Naftalenos/administración & dosificación , Naftalenos/efectos adversos , Oxipurinol/metabolismo , Oxipurinol/farmacocinética , Propionatos/administración & dosificación , Propionatos/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Ácido Úrico/sangre , Adulto JovenRESUMEN
BACKGROUND: The uric acid (UA) level in patients with gout is a key factor in disease management and is typically measured in the laboratory using plasma samples obtained after venous puncture. This study aimed to assess the reliability of immediate UA measurement with capillary blood samples obtained by fingertip puncture with the HumaSensplus point-of-care meter. METHODS: UA levels were measured using both the HumaSensplus meter in the clinic and the routine plasma UA method in the biochemistry laboratory of 238 consenting diabetic patients. HumaSensplus capillary and routine plasma UA measurements were compared by linear regression, Bland-Altman plots, intraclass correlation coefficient (ICC), and Lin's concordance coefficient. Values outside the dynamic range of the meter, low (LO) or high (HI), were analyzed separately. The best capillary UA thresholds for detecting hyperuricemia were determined by receiver operating characteristic (ROC) curves. The impact of potential confounding factors (demographic and biological parameters/treatments) was assessed. Capillary and routine plasma UA levels were compared to reference plasma UA measurements by liquid chromatography-mass spectrometry (LC-MS) for a subgroup of 67 patients. RESULTS: In total, 205 patients had capillary and routine plasma UA measurements available. ICC was 0.90 (95% confidence interval (CI) 0.87-0.92), Lin's coefficient was 0.91 (0.88-0.93), and the Bland-Altman plot showed good agreement over all tested values. Overall, 17 patients showed values outside the dynamic range. LO values were concordant with plasma values, but HI values were considered uninterpretable. Capillary UA thresholds of 299 and 340 µmol/l gave the best results for detecting hyperuricemia (corresponding to routine plasma UA thresholds of 300 and 360 µmol/l, respectively). No significant confounding factor was found among those tested, except for hematocrit; however, this had a negligible influence on the assay reliability. When capillary and routine plasma results were discordant, comparison with LC-MS measurements showed that plasma measurements had better concordance: capillary UA, ICC 0.84 (95% CI 0.75-0.90), Lin's coefficient 0.84 (0.77-0.91); plasma UA, ICC 0.96 (0.94-0.98), Lin's coefficient 0.96 (0.94-0.98). CONCLUSIONS: UA measurements with the HumaSensplus meter were reasonably comparable with those of the laboratory assay. The meter is easy to use and may be useful in the clinic and in epidemiologic studies.
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Recolección de Muestras de Sangre/instrumentación , Sistemas de Atención de Punto , Punciones/instrumentación , Ácido Úrico/sangre , Recolección de Muestras de Sangre/métodos , Femenino , Gota/sangre , Gota/diagnóstico , Humanos , Hiperuricemia/sangre , Hiperuricemia/diagnóstico , Masculino , Persona de Mediana Edad , Punciones/métodos , Curva ROC , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for treating gout and asymptomatic hyperuricaemia. This study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad in combination with febuxostat in adults with gout. METHODS: The phase IIa, open-label, multicentre study randomised 64 subjects into one of five cohorts to receive febuxostat (40 or 80 mg) alone or in combination with verinurad 2.5-20 mg. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events, chemistry panels, ECGs and physical examinations. RESULTS: Serum pharmacodynamic data demonstrated the maximum percent decrease in serum urate (sUA) from baseline (Emax) at 8-12 hours after dosing. Verinurad with febuxostat decreased sUA in a dose-dependent manner. Emax for verinurad with febuxostat 40 mg ranged from 52% to 77% vs 42% for febuxostat 40 mg alone; Emax for verinurad with febuxostat 80 mg was 62%-82% vs 55% for febuxostat 80 mg alone. Urinary uric acid excretion rate was reduced below baseline by febuxostat alone and was comparable to baseline for verinurad with febuxostat. Verinurad plasma exposure increased with dose and was comparable when combined with febuxostat. No drug-drug interactions were observed. Verinurad was well tolerated with no clinically meaningful changes in laboratory values. CONCLUSION: Verinurad administered with febuxostat produced dose-dependent decreases in sUA while maintaining urinary uric acid levels comparable to baseline. These dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. TRIAL REGISTRATION NUMBER: NCT02246673.
RESUMEN
OBJECTIVES: Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout. METHODS: Forty-one subjects were randomised into two cohorts of verinurad (2.5-20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone. Each treatment period was 7 days. Serial plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol and uric acid. RESULTS: Serum pharmacodynamic data pooled across cohorts demonstrated maximum per cent decreases in serum urate (sUA) from baseline (Emax) at 7-12 hours after verinurad plus allopurinol treatment. Combination treatment decreased sUA in dose-dependent manner: least-squares means Emax was 47%, 59%, 60%, 67%, 68% and 74% for verinurad doses 2.5, 5, 7.5, 10, 15 and 20 mg plus allopurinol 300 mg once daily, versus 40%, 54% and 54% for allopurinol 300 mg once daily, 600 mg once daily and 300 mg twice daily. Verinurad had no effect on allopurinol plasma pharmacokinetics, but decreased oxypurinol Cmax by 19.0%-32.4% and area under the plasma concentration-time curve from time zero to the last measurable time point by 20.8%-39.2%. Verinurad plus allopurinol was well tolerated with no serious adverse events (AEs), AE-related withdrawals or renal-related events. Laboratory values showed no clinically meaningful changes. CONCLUSION: Verinurad coadministered with allopurinol produced dose-dependent decreases in sUA. All dose combinations of verinurad and allopurinol were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. TRIAL REGISTRATION NUMBER: NCT02498652.
RESUMEN
This study assesses the efficacy and exposure-response relationship of omega-3-carboxylic acids (OM-3 CA) in models of crystal-based inflammation. Human THP-1 macrophages and primary peripheral blood mononuclear cells exposed to multiple inflammatory crystal types were used to determine the anti-inflammatory potential of omega-3 (OM-3) fatty acids in vitro. Anti-inflammatory effects of OM-3 CA in vivo were tested in rat monosodium urate (MSU) crystal air pouch and rat knee intra-articular MSU injection models. Acute treatment with the OM-3 fatty acid docosahexaenoic acid suppressed MSU-, cholesterol crystal-, and calcium pyrophosphate crystal-mediated interleukin-1ß (IL-1ß) production in vitro. In vivo, OM-3 CA dose-dependently reduced crystal-mediated cell migration, exudate volume, and levels of IL-1ß and prostaglandin E2. Following intra-articular injection of MSU, treatment with OM-3-CA (1 mL/kg) and indomethacin (1 mg/kg) resulted in similar mean reductions in pain (23% and 41%, respectively) and swelling (58% and 50%, respectively), compared with controls. Additionally, in complex formulations of OM-3 fatty acids, high levels of palmitic acid could reduce the in vivo effect on crystal-mediated IL-1ß elevation. OM-3 CA has a broadly efficacious anti-inflammatory effect with a strong exposure-response relationship that could be beneficial in prevention and treatment of crystal arthritis, with potential applications in other IL-1ß-mediated diseases.
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Antiinflamatorios/farmacología , Artritis Gotosa/etiología , Artritis Gotosa/metabolismo , Ácidos Carboxílicos/farmacología , Ácidos Grasos Omega-3 , Animales , Antiinflamatorios/química , Artritis Gotosa/tratamiento farmacológico , Artritis Gotosa/patología , Ácidos Carboxílicos/química , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Dinoprostona/biosíntesis , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Exudados y Transudados/metabolismo , Ácidos Grasos Omega-3/química , Ácidos Grasos Omega-3/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Leucocitos/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ácido Palmítico/farmacología , RatasRESUMEN
Objective: ABCG2 rs2231142 (Q141K) has been reported to be associated with poor response to allopurinol, while there are conflicting data on the association between the genetically independent ABCG2 rs10011796 variant and allopurinol response. The aim of this study was to replicate the association of ABCG2 rs2231142 and rs10011796 with allopurinol response and perform a meta-analysis. Methods: Participants in the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) (n = 299) were studied. In patients with evidence of adherence to allopurinol therapy (plasma oxypurinol >20 µmol/l), good response was defined as serum urate <6 mg/dl on allopurinol ⩽300 mg/day and poor response as serum urate ⩾ 6 mg/dl despite allopurinol >300 mg/day. Association of rs2231142 and rs10011796 with poor response was tested in logistic regression models that included age, sex, BMI, ethnicity and estimated glomerular filtration rate. Results from the LASSO study and a subset of participants in the Genetics of Gout in Aotearoa New Zealand study (n = 296, including 264 from a previously published report) were combined by meta-analysis. Results: There was evidence for association of rs2231142 with allopurinol response [odds ratio (OR) = 2.35, P = 7.3 × 10-4] but not for rs10011796 (OR = 1.21, P = 0.33) in the LASSO cohort using an adjusted logistic regression model. Meta-analysis provided evidence of a significant association of rs2231142 with allopurinol response (OR = 2.43, P = 6.2 × 10-7), but not rs10011796 (OR = 1.06, P = 0.69). Conclusion: This study has confirmed the significant association of ABCG2 rs2231142 with poor response to allopurinol.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Alopurinol/uso terapéutico , ADN/genética , Gota , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Predisposición Genética a la Enfermedad , Genotipo , Gota/tratamiento farmacológico , Gota/genética , Gota/metabolismo , Supresores de la Gota/uso terapéutico , Humanos , Proteínas de Neoplasias/metabolismoAsunto(s)
Alopurinol/sangre , Supresores de la Gota/sangre , Gota/tratamiento farmacológico , Cumplimiento de la Medicación/estadística & datos numéricos , Oxipurinol/sangre , Adulto , Alopurinol/uso terapéutico , Ensayos Clínicos como Asunto , Femenino , Supresores de la Gota/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Ácido Úrico/sangreRESUMEN
PURPOSE: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. SUBJECTS AND METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10-12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). RESULTS: A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner; Cmax occurred at 0.5-0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax by 37%-53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported. CONCLUSION: Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.
Asunto(s)
Ácido Úrico/metabolismo , Uricosúricos/farmacología , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Absorción Intestinal , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Ácido Úrico/orina , Uricosúricos/efectos adversos , Uricosúricos/farmacocinética , Adulto JovenRESUMEN
Gout is caused by elevated serum urate levels, which can be treated using inhibitors of the uric acid transporter, URAT1. Here, we characterize verinurad (RDEA3170), which is currently under evaluation for gout therapy. Verinurad specifically inhibits URAT1 with a potency of 25 nM. High affinity inhibition of uric acid transport requires URAT1 residues Cys-32, Ser-35, Phe-365 and Ile-481. Unlike other available uricosuric agents, the requirement for Cys-32 is unique to verinurad. Two of these residues, Ser-35 and Phe-365, are also important for urate transport kinetics. A URAT1 binding assay using radiolabeled verinurad revealed that distinct URAT1 inhibitors benzbromarone, sulfinpyrazone and probenecid all inhibit verinurad binding via a competitive mechanism. However, mutations made within the predicted transporter substrate channel differentially altered the potency for individual URAT1 inhibitors. Overall, our results suggest that URAT1 inhibitors bind to a common site in the core of the transporter and sterically hinder the transit of uric acid through the substrate channel, albeit with vastly different potencies and with differential interactions with specific URAT1 amino acids.
Asunto(s)
Gota/tratamiento farmacológico , Gota/metabolismo , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Transportadores de Anión Orgánico/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Uricosúricos/uso terapéutico , Adulto , Animales , Benzbromarona/farmacología , Benzbromarona/uso terapéutico , Transporte Biológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Concentración 50 Inhibidora , Cinética , Masculino , Terapia Molecular Dirigida , Mutación , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Unión Proteica , Ratas , Ácido Úrico/sangre , Ácido Úrico/metabolismo , Uricosúricos/farmacología , Adulto JovenRESUMEN
OBJECTIVE: Our objectives were to determine whether a change in serum uric acid (sUA) resulted in a corresponding change in the fractional excretion of uric acid (FEUA) and whether the renal response was different in patients with gout versus healthy subjects. METHODS: FEUA was calculated from previously published studies and four new phase I studies in healthy subjects and/or patients with gout before and after treatment to lower or raise sUA. Treatments included xanthine oxidase inhibitors to lower sUA as well as infusion of uric acid and provision of a high-purine diet to raise sUA. Plots were created of FEUA versus sUA before and after treatment. For the phase I studies, percent change in FEUA per mg/dL change in sUA was calculated separately for healthy subjects and patients with gout, and compared using Student's t test. RESULTS: Analysis of previously published data and the new phase I clinical data indicates that changing sUA by a non-renal mechanism leads to a change in FEUA. The magnitude of change is greater in subjects with higher baseline FEUA versus patients with gout. Healthy subjects excrete more urate than do patients with gout at physiological urate-filtered load; this difference disappears when the urate-filtered load is decreased to â¼5000mg/24hours. CONCLUSION: These observations are consistent with a less saturated urate reabsorption system in patients with gout versus healthy subjects, resulting in elevated retention of uric acid. Further investigation could lead to the discovery of mechanisms responsible for the etiology of hyperuricemia/gout.
Asunto(s)
Gota/sangre , Hiperuricemia/sangre , Riñón/fisiopatología , Ácido Úrico/sangre , Adulto , Anciano , Femenino , Gota/tratamiento farmacológico , Gota/metabolismo , Gota/fisiopatología , Supresores de la Gota/uso terapéutico , Voluntarios Sanos , Humanos , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/metabolismo , Hiperuricemia/fisiopatología , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Ácido Úrico/metabolismo , Ácido Úrico/orina , Xantina Oxidasa/antagonistas & inhibidores , Adulto JovenRESUMEN
Humans and higher primates are unique in that they lack uricase, the enzyme capable of oxidizing uric acid. As a consequence of this enzyme deficiency, humans have high serum uric acid levels. In some people, uric acid levels rise above the solubility limit resulting in crystallization in joints, acute inflammation in response to those crystals causes severe pain; a condition known as gout. Treatment for severe gout includes injection of non-human uricase to reduce serum uric acid levels. Krystexxa® is a hyper-PEGylated pig-baboon chimeric uricase indicated for chronic refractory gout that induces an immunogenic response in 91% of treated patients, including infusion reactions (26%) and anaphylaxis (6.5%). These properties limit its use and effectiveness. An innovative approach has been used to develop a therapeutic uricase with improved properties such as: soluble expression, neutral pH solubility, high E. coli expression level, thermal stability, and excellent activity. More than 200 diverse uricase sequences were aligned to guide protein engineering and reduce putative sequence liabilities. A single uricase lead candidate was identified, which showed low potential for immunogenicity in >200 human donor samples selected to represent diverse HLA haplotypes. Cysteines were engineered into the lead sequence for site specific PEGylation and studies demonstrated >95% PEGylation efficiency. PEGylated uricase retains enzymatic activity in vitro at neutral pH, in human serum and in vivo (rats and canines) and has an extended half-life. In canines, an 85% reduction in serum uric acid levels was observed with a single subcutaneous injection. This PEGylated, non-immunogenic uricase has the potential to provide meaningful benefits to patients with gout.