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1.
AAPS PharmSciTech ; 23(1): 43, 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34964923

RESUMO

Co-crystallization studies were undertaken to improve the solubility of a highly water-insoluble drug febuxostat (FXT), used in the treatment of gout and hyperuricemia. The selection of co-crystal former (CCF) molecules such as 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SAC), 5-nitro isophthalic acid (5-NPH), isonicotinamide (ISNCT), and picolinamide (PICO) was based on the presence of complementary functional groups capable of forming hydrogen bond and the ΔpKa difference between FXT and CCF. A liquid-assisted grinding (LAG) method was successfully employed for the rapid screening of various pharmaceutical adducts. These adducts were characterized based on their unique thermal (differential scanning calorimetry) and spectroscopic (Fourier transform infrared and Raman spectroscopy) profiles. Binary phase diagrams (BPD) were plotted to establish a relationship between the thermal events and adduct formed. Powder X-ray diffraction (PXRD) studies were carried out to confirm the formation of eutectic/co-crystal. Thermogravimetric analysis (TGA) was also performed for the novel co-crystals obtained. The propensity for strong homo-synthons over weak hetero-synthons and strong hetero-synthons over weak homo-synthons during supramolecular growth resulted in the formation of eutectics and co-crystals respectively. FXT:1H-2NPH (1), FXT:4-HBA (1), FXT:SAC (1, 2), and FXT:5-NPH (2-1) gave rise to pure eutectic systems, while FXT:ISNCT (2-1) and FXT:PICO (1) gave rise to novel co-crystals with characteristic DSC heating curves and PXRD pattern. Additionally, the impact of microenvironmental pH and microspeciation profile on the improved dissolution profile of the co-crystals was discussed. Graphical Abstract.


Assuntos
Febuxostat , Varredura Diferencial de Calorimetria , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
2.
J Int Med Res ; 49(12): 3000605211062770, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34914568

RESUMO

OBJECTIVE: Heart failure (HF) is a common and highly morbid cardiovascular disorder. Oxidative stress worsens HF, and uric acid (UA) is a useful oxidative stress marker. The novel anti-hyperuricemic drug febuxostat is a potent non-purine selective xanthine oxidase inhibitor. The present study examined the UA-lowering and prognostic effects of febuxostat in patients with HF compared with conventional allopurinol. METHODS: This multicenter, randomized trial included 263 patients with chronic HF who were randomly assigned to two groups and received allopurinol or febuxostat (UA >7.0 mg/dL). All patients were followed up for 3 years after enrollment. RESULTS: There were no significant differences in baseline clinical characteristics between the two groups. The UA level was significantly decreased after 3 years of drug administration compared with the baseline in both groups. Urine levels of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine were lower in the febuxostat group than in the allopurinol group (11.0 ± 9.6 vs. 22.9 ± 15.9 ng/mL), and the rate of patients free from hospitalization due to worsening HF tended to be higher in the febuxostat group than in the allopurinol group (89.0% vs. 83.0%). CONCLUSIONS: Febuxostat is potentially more effective than allopurinol for treating patients with chronic HF and hyperuricemia.This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/; ID: 000009817).


Assuntos
Insuficiência Cardíaca , Hiperuricemia , Alopurinol/uso terapêutico , Febuxostat/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hiperuricemia/tratamento farmacológico , Ácido Úrico
3.
Trials ; 22(1): 743, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702311

RESUMO

BACKGROUND: The prevalence of renal calculi in patients with gout is high. Alkalized urine has been recommended by the 2020 European Association of Urology (EAU) guidelines to promote calculus dissolution. However, randomized controlled trials are lacking. METHODS: In the protocol of this randomized, placebo-controlled, double-blinded trial, patients with gout combined with renal calculi are randomized (1:1) to the placebo and sodium bicarbonate groups. The intervention would be performed for 24 weeks, the 1-12 weeks are double-blinded, and the 13-24 weeks are open-labeled. Sodium bicarbonate (1 g tid) will be performed for 24 weeks in the sodium bicarbonate group. The placebo will be performed for 12 weeks and not be performed from 13 weeks to 24 weeks in the placebo group. All subjects will be administered febuxostat (40 mg/day) for 24 weeks and receive concomitant anti-inflammatory prophylaxis therapy for 12 weeks. The primary outcome is the proportion of patients whose renal calculus volume will be reduced after 12 weeks of treatment. The secondary outcomes include the volume changes of renal calculi, uric acid changes, the proportion of patients with serum uric acid (sUA) levels < 360 µmol/L, the changes in estimated glomerular filtration rate (eGFR), the pH value of urine, and the incidence of adverse events after treatment for 12 and 24 weeks. DISCUSSION: This study will evaluate the efficacy and safety of sodium bicarbonate-alkalized urine on renal calculi in patients with gout. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR2100045183. Registered on April 7, 2021, with ChiCTR.


Assuntos
Gota , Cálculos Renais , Método Duplo-Cego , Febuxostat/uso terapêutico , Gota/diagnóstico , Gota/tratamento farmacológico , Supressores da Gota/uso terapêutico , Humanos , Cálculos Renais/diagnóstico , Cálculos Renais/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ácido Úrico
7.
Ann Palliat Med ; 10(10): 10327-10337, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34498481

RESUMO

BACKGROUND: To evaluate the major cardiovascular (CV) events of febuxostat compared to allopurinol for the treatment of gout or asymptomatic hyperuricemia. METHODS: Relevant studies published until August 15, 2020 were identified by a systematic search of the PubMed and Wiley Online Library databases. Any controlled clinical trial, randomised controlled trial (RCT), retrospective cohort study or open label trial (OLT) comparing febuxostat in patients with gout or hyperuricemia with allopurinol. The quality of all identified studies was assessed based on Cochrane Collaboration's risk of bias tool. Odds ratios (OR) were calculated with random effects and reported with corresponding 95% confidence intervals (CI). RESULTS: Eighteen studies were ultimately included in the analysis, among them 6 articles mentioned serum uric acid (sUA) level before and after treatment, 14 articles mentioned major cardiovascular events, 5 articles mentioned cardiovascular death, 6 articles mentioned skin reactions, 6 articles mentioned musculoskeletal and connective tissue signs and symptoms, 4 articles mentioned joint-related signs and symptoms, 6 articles mentioned upper respiratory infection, 5 articles mentioned gastrointestinal reaction and 7 articles mentioned all-cause mortality. The febuxostat group showed significantly lower sUA levels than allopurinol group (MD =-0.83, 95% CI: -1.22 to -0.44, P<0.0001, I2=98%). There was no markedly difference between the febuxostat and allopurinol (OR 1.01, 95% CI: 0.83 to 1.23, P=0.84, I2=95%) in the major cardiovascular events. The occurrence of skin reactions of febuxostat was significantly fewer than allopurinol (OR 0.55, 95% CI: 0.42 to 0.73, P<0.0001, I2=49%). Regarding to occurrence of CV death, musculoskeletal and connective tissue signs and symptoms, febuxostat group was higher than allopurinol group. However, among patients with gout or hyperuricemia, treatment with febuxostat resulted in other adverse reactions, including all-causes mortality similar to those associated with allopurinol. DISCUSSION: The limitation of the study was the included studies show high heterogeneity in regard to their design. There was no difference in the incidence of major cardiovascular events between febuxostat and allopurinol, and febuxostat was better in lowering uric acid and has less adverse skin reactions than allopurinol, but the risk of CV death of febuxostat was higher than allopurinol.


Assuntos
Doenças Cardiovasculares , Gota , Hiperuricemia , Alopurinol/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/tratamento farmacológico , Febuxostat/efeitos adversos , Gota/tratamento farmacológico , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/tratamento farmacológico , Resultado do Tratamento , Ácido Úrico
8.
Cochrane Database Syst Rev ; 8: CD010069, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34379791

RESUMO

BACKGROUND: Tophi develop in untreated or uncontrolled gout. This is an update of a Cochrane Review first published in 2014.  OBJECTIVES: To assess the benefits and harms of non-surgical and surgical treatments for the management of tophi in gout. SEARCH METHODS: We updated the search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases to 28 August 2020. SELECTION CRITERIA: We included all published randomised controlled trials (RCTs) or controlled clinical trials examining interventions for tophi in gout in adults. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included one trial in our original review. We added four more trials (1796 participants) in this update. One had three arms; pegloticase infusion every two weeks (biweekly), monthly pegloticase infusion (pegloticase infusion alternating with placebo infusion every two weeks) and placebo. Two studies looked at lesinurad 200 mg or 400 mg in combination with allopurinol. One trial studied lesinurad 200 mg or 400 mg in combination with febuxostat. One trial compared febuxostat 80 mg and 120 mg to allopurinol. Two trials were at unclear risk of performance and detection bias due to lack of information on blinding of participants and personnel. All other trials were at low risk of bias. Moderate-certainty evidence (downgraded for imprecision; one study; 79 participants) showed that biweekly pegloticase resolved tophi in 21/52 participants compared with 2/27 on placebo (risk ratio (RR) 5.45, 95% confidence interval (CI) 1.38 to 21.54; number needed to treat for a benefit (NNTB) 3, 95% CI 2 to 6). Similar proportions of participants receiving biweekly pegloticase (80/85) had an adverse event compared to placebo (41/43) (RR 0.99, 95% CI 0.91 to 1.07). However, more participants on biweekly pegloticase (15/85) withdrew due to an adverse event compared to placebo (1/43) (RR 7.59, 95% CI 1.04 to 55.55; number needed to treat for a harm (NNTH) 7, 95% CI 4 to 16). More participants on monthly pegloticase (11/52) showed complete resolution of tophi compared with placebo (2/27) (RR 2.86, 95% CI 0.68 to 11.97; NNTB 8, 95% CI 4 to 91). Similar numbers of participants on monthly pegloticase (84/84) had an adverse event compared to placebo (41/43) (RR 1.05, 95% CI 0.98 to 1.14). More participants on monthly pegloticase (16/84) withdrew due to adverse events compared to placebo (1/43) (RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14). Infusion reaction was the most common reason for withdrawal. Moderate-certainty evidence (2 studies; 103 participants; downgraded for imprecision) showed no clinically significant difference for complete resolution of target tophus in the lesinurad 200 mg plus allopurinol arm (11/53) compared to the placebo plus allopurinol arm (16/50) (RR 0.40, 95% CI 0.04 to 4.57), or in the lesinurad 400 mg plus allopurinol arm (12/48) compared to the placebo plus allopurinol arm (16/50) (RR 0.79, 95% CI 0.42 to 1.49). An extension study examined lesinurad 200 mg or 400 mg in combination with febuxostat, or placebo (low-certainty evidence, downgraded for indirectness and imprecision). Participants on lesinurad in the original study continued (CONT) on the same dose. Lesinurad 400 mg plus febuxostat may be beneficial for tophi resolution; 43/65 in the lesinurad 400 mg CONT arm compared to 38/64 in the lesinurad 200 mg CONT arm had tophi resolution (RR 1.11, 95% CI 0.85 to 1.46). Lesinurad 400 mg plus febuxostat may result in no difference in adverse events; 57/65 in the lesinurad 400 mg CONT arm had an adverse event compared to 50/64 in lesinurad 200 mg CONT arm (RR 1.12, 95% CI 0.96 to 1.32). Lesinurad 400 mg plus febuxostat may result in no difference in withdrawals due to adverse events; 10/65 participants in the lesinurad 400 mg CONT arm withdrew due to an adverse event compared to 10/64 participants in the lesinurad 200 mg CONT arm (RR 0.98, 95% CI 0.44 to 2.20). Lesinurad 400 mg plus febuxostat may result in no difference in mean serum uric acid (sUA), which was 3 mg/dl in the lesinurad 400 mg CONT group compared to 3.9 mg/dl in the lesinurad 200 mg CONT group (mean difference -0.90, 95% CI -1.51 to -0.29). Participants who were not on lesinurad in the original study were randomised (CROSS) to lesinurad 200 mg or 400 mg, both in combination with febuxostat. Low-certainty evidence downgraded for indirectness and imprecision showed that lesinurad 400 mg (CROSS) may result in tophi resolution (17/34) compared to lesinurad 200 mg (CROSS) (14/33) (RR 1.18, 95% CI 0.70 to 1.98). Lesinurad 400 mg in combination with febuxostat may result in no difference in adverse events (33/34 in the lesinurad 400 mg CROSS arm compared to 27/33 in the lesinurad 200 mg (CROSS); RR 1.19, 95% CI 1.00 to 1.41). Lesinurad 400 mg plus febuxostat may result in no difference in withdrawals due to adverse events, 5/34 in the lesinurad 400 mg CROSS arm withdrew compared to 2/33 in the lesinurad 200 mg CROSS arm (RR 2.43, 95% CI 0.51 to 11.64). Lesinurad 400 mg plus febuxostat results in no difference in sUA (4.2 mg/dl in lesinurad 400 mg CROSS) compared to lesinurad 200 mg (3.8 mg/dl in lesinurad 200 mg CROSS), mean difference 0.40 mg/dl, 95% CI -0.75 to 1.55. AUTHORS' CONCLUSIONS: Moderate-certainty evidence showed that pegloticase is probably beneficial for resolution of tophi in gout. Although there was little difference in adverse events when compared to placebo, participants on pegloticase had more withdrawals due to adverse events. Lesinurad 400 mg plus febuxostat may be beneficial for tophi resolution compared with lesinurad 200 mg plus febuxostat; there was no difference in adverse events between these groups. We were unable to determine whether lesinurad plus febuxostat is more effective than placebo. Lesinurad (400 mg or 200 mg) plus allopurinol is probably not beneficial for tophi resolution, and there was no difference in adverse events between these groups. RCTs on interventions for managing tophi in gout are needed, and the lack of trial data is surprising given that allopurinol is a well-established treatment for gout.


Assuntos
Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Urato Oxidase/uso terapêutico , Alopurinol/uso terapêutico , Febuxostat/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tioglicolatos/uso terapêutico , Triazóis/uso terapêutico
9.
Biomed Pharmacother ; 139: 111664, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243606

RESUMO

The accurate quantitative determination of affinity and binding kinetics (BK) for tight binding inhibition is extraordinary important from both the continuous optimization of compounds, particularly in developing structure-activity relationships (SAR), and the prediction of in vivo target occupancy (TO). Due to the unique properties for tight binding inhibition that the inhibitors are characterized by the ultrahigh-affinity, relatively fast association to the target enzyme combined with extremely slow dissociation of the inhibitor-enzyme binary complex, the classical steady state equilibrium methods are no longer valid. Here, we made several recommendations of how to design the optimal experiments and apply special mathematical calculation approaches to quantitatively evaluate the accurate affinity and BK as the examples of two tight binding inhibitors against the xanthine oxidase (XO), as well as compared the differences in the results calculated from the different data analytical methods and analyzed the influence of these differences on the XO engagement in human. Analysis of the results displayed that the accurate apparent dissociation constant (Ki*,app) was 0.2 ± 0.06 nM for topiroxotstat and was 0.45 ± 0.2 nM for febuxostat; that on-rate (kon) was (4.3 ± 1.1) × 106 M-1s-1 for topiroxotstat and was(133.3 ± 3.5) × 106 M-1s-1 for febuxostat, and off-rate (koff) was (1.0±0.2) × 10-5 s-1 for topiroxotstat and was ≤ 0.16 × 10-5 s-1for febuxostat. Moreover, there were significant differences in the Ki*,app and koff values estimated using the appropriate specialized methods for tight binding inhibition versus classical steady state equilibrium methods, with the substantial differences of 14-fold and 32-fold reduction for topiroxostat, respectively, and of 9.6-fold and ≥ 213-fold reduction for febuxostat, while the kon values remain the moderate differences for the two inhibitors. The obvious greater AUC of XO engagement time courses and longer durations of above 70% engagement by the appropriate specialized methods for tight binding inhibition were observed that the results display the differences of 70.1% and 88%, respectively for topiroxostat and of 38.1% and 35.0%, respectively for febuxostat in human liver cell than by classical steady state equilibrium methods. Again, our studies provide several valuable recommendations of the optimal experiment protocols and appropriate analytical approaches for accurately quantitatively assessing the affinity and BK parameters as well as demonstrate the ability of our recommended methods to generate reliable data for tight binding inhibitors against XO.


Assuntos
Inibidores Enzimáticos/farmacologia , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo , Células Cultivadas , Febuxostat/farmacologia , Humanos , Cinética , Ligação Proteica/fisiologia , Relação Estrutura-Atividade
10.
Int J Mol Sci ; 22(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34281235

RESUMO

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.


Assuntos
Febuxostat/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Neurotransmissores/uso terapêutico , Risperidona/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Animais , Corpo Caloso/efeitos dos fármacos , Cuprizona , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Febuxostat/farmacologia , Feminino , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neurotransmissores/farmacologia , Risperidona/farmacologia , Canal de Cátion TRPA1/efeitos dos fármacos , Cloridrato de Venlafaxina/farmacologia
11.
Drug Deliv ; 28(1): 1321-1333, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34176376

RESUMO

Febuxostat (FXS) is a potent antigout drug with poor water solubility and relative high first-pass effect leading to moderate oral bioavailability (<49%). This study aimed to increase FXS solubility and bioavailability by optimizing sublingual fast-dissolving films (SFs) containing a selected FXS self-nano-emulsifying system (s-SNES) previously prepared by our team. The s-SNES was loaded into SFs by solvent casting technique. A full factorial design (32) was applied to study the effects of polymer and plasticizer types on mechanical characteristics and the dissolution profile of FXS from the SFs. Numerical optimization was performed to select the SF having highest desirability according to predetermined characteristics. The optimized SF (O-SF) contained 1 g of s-SNES, polyvinylpyrrolidone K30 (6%w/v), polyethylene glycol 300 (20%w/w of polymer wt.), and Avicel PH101 (0.5%w/v). O-SF showed good permeation of FXS through sheep sublingual tissue. Storage of O-SF for three months showed no significant change in the FXS dissolution profile. In-vivo performance of O-SF in rabbits was compared to that of oral marketed tablets (Staturic® 80 mg). A cross-over design was applied and pharmacokinetic parameters were calculated after ensuring absence of sequence effect. Statistical analysis revealed better performance for O-SF with significantly higher Cmax, AUC0-24, AUC0-∞, apparent t1/2 together with lower tmax, and apparent kel than marketed tablets. Relative bioavailability of O-SF compared to the marketed tablet was found to be 240.6%. This confirms the achievement of the study aims of improving dissolution rate and bioavailability of FXS using a patient-wise convenient formula.


Assuntos
Portadores de Fármacos/química , Febuxostat/farmacocinética , Supressores da Gota/farmacocinética , Nanopartículas/química , Animais , Área Sob a Curva , Química Farmacêutica , Estudos Cross-Over , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões , Febuxostat/administração & dosagem , Supressores da Gota/administração & dosagem , Meia-Vida , Tamanho da Partícula , Coelhos , Ovinos , Solubilidade , Tensoativos/química
13.
Am J Kidney Dis ; 78(3): 468, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34126127
14.
Expert Rev Clin Pharmacol ; 14(8): 1039-1050, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34030558

RESUMO

OBJECTIVES: This study was conducted to evaluate the potential nephroprotective effects of febuxostat, mirtazapine, and their combination against gentamicin-induced nephrotoxicity. METHODS: Induction of nephrotoxicity was achieved via gentamicin injection (100 mg/kg, I.P., for 7 days). Two different doses of mirtazapine (15-30 mg/kg), febuxostat (5-10 mg/kg), and their combination were administered daily for 14 days prior to gentamicin injection and then concomitantly with gentamicin for additional 7 days. Nephrotoxicity was evaluated histopathologically and biochemically. Renal caspase-3, extracellular signal-regulated protein kinase 1/2 (ERK1/2), nuclear factor-kappa-ß (NF-κß), and monocyte chemoattractant protein (MCP-1) were assayed. RESULTS: Febuxostat and mirtazapine significantly (p < 0.05) alleviated biochemical and histopathological alterations that were induced by gentamicin and, for the first time, significantly decreased the renal levels of ERK1/2 and MCP-1. Conclusion: Febuxostat and mirtazapine were found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity. EXPERT OPINION: The utility of nonpurine xanthine oxidase inhibitor, such as febuxostat and mirtazapine are offering a new potential opportunity for the future nephroprotective effects therapy: Febuxostat and mirtazapine are found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity.


Assuntos
Febuxostat/farmacologia , Gentamicinas/toxicidade , Nefropatias/prevenção & controle , Mirtazapina/farmacologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/toxicidade , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Quimiocina CCL2/metabolismo , Sinergismo Farmacológico , Febuxostat/administração & dosagem , Gentamicinas/administração & dosagem , Supressores da Gota/administração & dosagem , Supressores da Gota/farmacologia , Nefropatias/induzido quimicamente , Masculino , Mirtazapina/administração & dosagem , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ratos
15.
Clin Cardiol ; 44(7): 907-916, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34013998

RESUMO

The cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout remains equivocal. Febuxostat had a better safety outcome compared with allopurinol. In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2000 and April 4, 2021, without any language restrictions. We did a systematic review and meta-analysis of included clinical trials to evaluate the cardiovascular safety of febuxostat compared to allopurinol for treatment of chronic gout. Two reviewers independently selected studies, assessed study quality, and extracted data. Risk ratios were calculated with random effects and were reported with corresponding 95% confidence intervals (CI). From 240 potentially relevant citations, 224 papers were excluded; 16 studies were ultimately included in the analysis. Febuxostat had a better safety outcome compared with allopurinol,which was the composite of urgent coronary revascularization (OR: 0.84, 95% CI: 0.77-0.90, p < .0001) and stroke (OR: 0.87, 95% CI: 0.79-0.97, p = .009). However, that difference was not found in nonfatal myocardial infarction (OR: 0.99, 95% CI: 0.80-1.22, p = .91), cardiovascular related mortality (OR: 0.98, 95% CI: 0.69-1.38, p = .89) and all-cause mortality (OR: 0.93, 95% CI: 0.75-1.15, p = .52). No significant differences in cardiovascular related mortality and all-cause mortality were observed across any subgroup. This meta-analysis adds new evidence regarding the cardiovascular safety of febuxostat in patients. Initiation of febuxostat in patients was not associated with an increased risk of death or serious cardiovascular related adverse events compared with allopurinol.


Assuntos
Gota , Hiperuricemia , Infarto do Miocárdio , Alopurinol/efeitos adversos , Febuxostat/efeitos adversos , Gota/diagnóstico , Gota/tratamento farmacológico , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico
16.
Bioorg Chem ; 113: 104948, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34052736

RESUMO

Various febuxostat derivatives comprising carboxamide functionalities and different substituted heterocycles were synthesized and evaluated for their biological activities as xanthine oxidase (XO) and cyclooxygenase (COX) inhibitors. All the tested compounds exhibited variable in vitro XO inhibitory activities (IC50 values 0.009-0.077 µM), among which the analog 17 has emerged as the most potent derivative (IC50 0.009 µM), representing nearly 3-times the potency of febuxostat (IC50 0.026 µM). The same analogs were further investigated for their in vitro COX-1 and COX-2 inhibitory activity, where fifteen analogs demonstrated recognizable COX-2 inhibitory potential (IC50 values range 0.04 - 0.1 µM), when correlated with celecoxib (IC50 0.05 µM), together with appreciable selectivity indices. Compounds 5a, 14b, 17, 19c, 19e and 21b that showed significant in vitro XO and/ or COX inhibitory potentials were further investigated for their in vivo hypouricemic as well as anti-inflammatory activities. Interestingly, the in vivo results were concordant with the collected in vitro data. Docking of compounds 5a, 14b, 17, 19c, 19e and 21b with the active sites of XO and COX-2 isozymes demonstrated superior binding profile compared with the reported ligands (febuxostat and celecoxib, respectively). Their docking scores were reasonable and cohering to a great extent with their corresponding in vitro IC50 values. Moreover, in silico computation of the predicted pharmacokinetic and toxicity properties (ADMET), together with the ligand efficiency (LE) of the same six compounds suggesting their liability to act as new orally active drug candidates with a predicted high safety profile.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores Enzimáticos/farmacologia , Febuxostat/farmacologia , Compostos Heterocíclicos/farmacologia , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carragenina , Bovinos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Febuxostat/síntese química , Febuxostat/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Ovinos , Relação Estrutura-Atividade , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
17.
Expert Opin Pharmacother ; 22(11): 1397-1406, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33926357

RESUMO

INTRODUCTION: Gout is an inflammatory disease triggered by deposition of urate crystals secondary to longstanding hyperuricemia, and its management implies both the treatment of flares and management of hyperuricemia. Dotinurad is a selective urate reabsorption inhibitor (SURI), potently inhibits urate transporter 1 in the apical surface of renal proximal tubular cells, and has been approved for the treatment of gout and hyperuricemia in Japan. AREAS COVERED: This overview of dotinurad covers nonclinical and clinical pharmacology studies in special populations and its efficacy and safety in Japanese hyperuricemic patients with and without gout. EXPERT OPINION: Dotinurad, as an SURI, is expected to inhibit urate reabsorption more effectively than conventional urate-lowering agents. It is noninferior to benzbromarone or febuxostat in reducing serum urate levels in hyperuricemic patients with or without gout. Its efficacy is not attenuated in patients with mild to moderate renal impairment or with hepatic impairment. At a maintenance dose of 2 or 4 mg once daily, most patients achieved the target serum urate level of ≤6 mg/dL in a long-term study. No findings that raised safety concerns, including liver injury, were identified. Dotinurad is expected to be a new therapeutic option in hyperuricemic patients with and without gout.


Assuntos
Gota , Hiperuricemia , Benzotiazóis , Febuxostat/uso terapêutico , Gota/tratamento farmacológico , Supressores da Gota/uso terapêutico , Humanos , Hiperuricemia/tratamento farmacológico , Ácido Úrico , Uricosúricos/uso terapêutico
18.
Ned Tijdschr Geneeskd ; 1652021 04 26.
Artigo em Holandês | MEDLINE | ID: mdl-33914423

RESUMO

The treatment of gout is subject to different national and international guidelines. These guidelines differ in the extent to which they consider cardiovascular risk factors when deciding to start allopurinol. Observational studies and limited trial data suggest that treatment with allopurinol may reduce the risk of cardiovascular events in patients with gout. However, at this moment allopurinol remains an unproven strategy. There is need for a large randomized placebo-controlled trial with sufficient power and duration of follow-up.


Assuntos
Alopurinol/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Febuxostat/uso terapêutico , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Fatores de Risco
19.
Ultrasound Med Biol ; 47(6): 1495-1505, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33785225

RESUMO

This prospective study was aimed at observing the changes in three ultrasound (US) outcome domains (urate deposition, joint inflammation and bone erosion) in gout patients within the 1 y on urate-lowering therapy. The elementary lesions, including tophus, double-contour (DC) sign, aggregates, synovitis and bone erosion of the bilateral knee, ankle and first metatarsophalangeal joints, were evaluated repeatedly by US before and after 3, 6 and 12 mo of treatment, and the effective rates of clearance of tophus, DC sign and aggregates in different time groups were compared. A Global OMERACT-EULAR Synovitis Score (GLOESS) was calculated for these three paired joints to observe the inflammation. Bone erosion was also scored. The correlation between serum uric acid levels and tophus size changes was analyzed. Our results indicated that the decrease in serum uric acid levels was not completely parallel to the decrease in tophus size. For tophus, there was no significant difference in the clearance rate between different time groups (χ2 = 1.76, p = 0.392), while for DC sign and aggregates, there were significant differences (χ2 = 21.48, p < 0.001, χ2 = 7.75, p = 0.018). Meanwhile, GLOESS was significantly lower after 6 mo of therapy (χ2 = 32.316, p < 0.001). Additionally, bone erosion had not improved after 1 y of treatment (Z = -1.633, p = 0.102). Thus, US is crucial for assessing response to urate-lowering therapy in gout.


Assuntos
Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Gota/diagnóstico por imagem , Gota/tratamento farmacológico , Adulto , Artrite/etiologia , Doenças Ósseas/etiologia , Feminino , Seguimentos , Gota/complicações , Gota/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sinovite/etiologia , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia , Ácido Úrico/metabolismo
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