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1.
J Biomed Nanotechnol ; 17(10): 2071-2084, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34706807

RESUMO

Uric acid is the final product of purine metabolism, and excessive serum uric acid can cause gouty arthritis and uric acid nephropathy. Therefore, lowering the uric acid level and alleviating inflammation in the body are the key points to treating these diseases. A stable nanosuspension of peptide BmK9 was prepared by the precipitation-ultrasonication method. By combining uricase on the surface of a positively charged carrier, a complex consisting of neutral rod-shaped BmK9 and uricase nanoparticles (Nplex) was formed to achieve the delivery of BmK9 and uricase, respectively. The formulation of Nplex has a diameter of 180 nm and drug loading up to 200%, which releases BmK9 and uricase slowly and steadily in drug release tests in vitro. There was significantly improved pharmacokinetic behavior of the two drugs because Nplex prolonged the half-life and increased tissue accumulation. Histological assessments showed that the dual drug Nplex can reduce the inflammation response in acute gouty arthritis and chronic uric acid nephropathy in vivo. In the macrophage system, there was lower toxicity and increased beneficial effect on inflammation with Nplex than free BmK9 or uricase. Collectively, this novel formulation provides a dual drug delivery system that can treat gouty arthritis and uric acid nephropathy.


Assuntos
Artrite Gotosa , Nefropatias , Nanopartículas , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Humanos , Urato Oxidase , Ácido Úrico
2.
Nanoscale ; 13(30): 13014-13023, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477784

RESUMO

A facile one-pot precipitation method was employed to prepare a petal-shaped hybrid under mild conditions. The hybrid is composed of urate oxidase (UOx) encapsulated into a zeolite-like metal-organic framework (MOF) with the doping of a hollow gold nanocage (AuNC). As one of the MOF-enzyme composites, a UOx@MOF(AuNC) hybrid with the features of artificial nanoenzymes was developed as a novel dual-channel biosensing platform for fluorescence (FL) and electrochemical detection of uric acid (UA). As for FL biosensing, enzymatic catalysis of the hybrid in the presence of UA triggered tandem catalysis and oxidation reactions to cause FL quenching. UA was linearly detected in the 0.1-10 µM and 10-300 µM ranges, with the limit of detection (LOD) of 20 nM. As for electrochemical biosensing, the hybrid was dropped on a glassy carbon electrode (GCE) surface to construct a hybrid/GCE platform. Based on the redox reaction of UA on the platform surface, UA was linearly detected in the 0.05-55 µM range, with a LOD of 15 nM. Experimental results confirmed that the hybrid-based dual-channel biosensing platform enabled selective and sensitive responses to UA over potential interferents. The platform has an excellent detection capability in physiological samples. The dual-channel biosensing platform facilitates the exploration of new bioanalysis techniques for early clinical diagnosis of diseases.


Assuntos
Técnicas Biossensoriais , Estruturas Metalorgânicas , Catálise , Técnicas Eletroquímicas , Eletrodos , Ouro , Limite de Detecção , Urato Oxidase
3.
J Control Release ; 338: 804-812, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34481925

RESUMO

Pegloticase is an enzyme used to reduce serum uric acid levels in patients with chronic, treatment-refractory gout. Clinically, about 40% of patients develop high titers of anti-PEG antibodies (APA) after initial treatment, which in turn quickly eliminate subsequent doses of pegloticase from the systemic circulation and render the treatment ineffective. We previously found that pre-infusion with high MW free PEG (40 kDa) can serve as a decoy to saturate circulating APA, preventing binding to a subsequently administered dose of PEG-liposomes and restoring their prolonged circulation in mice, without any detectible toxicity. Here, we investigated the use of 40 kDa free PEG to restore the circulation of radio-labeled pegloticase in mice using longitudinal Positron Emission Tomography (PET) imaging over 4 days. Mice injected with pegloticase developed appreciable APA titers by Day 9, which further increased through Day 14. Compared to naïve mice, mice with pegloticase-induced APA rapidly cleared 89Zr-labeled pegloticase, with ~75% lower pegloticase concentrations in the circulation at four hours after treatment. The 96-h AUC in APA+ mice was less than 30% of the AUC in naïve mice. In contrast, pre-infusion of free PEG into PEG-sensitized mice restored the AUC of pegloticase to ~80% of that seen in naïve mice, resulting in a similar biodistribution to pegloticase in naïve mice over time. These results suggest that pre-infusion of free PEG may be a promising strategy to enable the safe and efficacious use of pegloticase and other PEGylated drugs in patients that have previously failed therapy due to induced APA.


Assuntos
Gota , Animais , Humanos , Camundongos , Polietilenoglicóis , Distribuição Tecidual , Urato Oxidase , Ácido Úrico
4.
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
5.
Enzyme Microb Technol ; 149: 109852, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34311889

RESUMO

As evidences showed that UOX(Gene ID: 391051), a single pseudogene formed after multiple mutations during human evolution, could be transcribed to mature mRNA and translated to two short peptides, we hypothesized that urate oxidase with higher homology with deduced human urate oxidase (dHU) might have lower immunogenicity. In this work, we constructed a "resurrected" human-source urate oxidase (rHU19) based on dHU. It obtained better uricolytic activity (8.29 U/mg) and catalytic efficiency (3.32 s-1 µM-1) compared with wild porcine urate oxidase (wPU) and FDA-approved porcine-baboon chimera (PBC). Maintaining high homology with dHU (93.75 %), rHU19 could be more suitable for the treatment of gout and hyperuricemia theoretically.


Assuntos
Hiperuricemia , Urato Oxidase , Animais , Expressão Gênica , Humanos , Hiperuricemia/genética , Suínos , Urato Oxidase/genética
7.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070642

RESUMO

Urate oxidase initiates the uric acid degradation pathways and is extensively used for protein drug development for gout therapy and serum uric acid diagnosis. We first present the biochemical and structural elucidation of a urate oxidase from the extremophile microorganism Deinococcus radiodurans (DrUox). From enzyme characterization, DrUox showed optimal catalytic ability at 30 °C and pH 9.0 with high stability under physiological conditions. Only the Mg2+ ion moderately elevated its activity, which indicates the characteristic of the cofactor-free urate oxidase family. Of note, DrUox is thermostable in mesophilic conditions. It retains almost 100% activity when incubated at 25 °C and 37 °C for 24 h. In this study, we characterized a thermostable urate oxidase, DrUox with high catalytic efficiency and thermal stability, which strengthens its potential for medical applications.


Assuntos
Proteínas de Bactérias , Deinococcus , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Urato Oxidase , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/uso terapêutico , Deinococcus/enzimologia , Deinococcus/genética , Humanos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Urato Oxidase/química , Urato Oxidase/genética , Urato Oxidase/uso terapêutico
8.
Leuk Res ; 107: 106588, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33957371

RESUMO

BACKGROUND: Rasburicase can markedly and rapidly decrease uric acid (UA) levels, thereby preventing and treating tumor lysis syndrome. However, rasburicase is expensive, especially when used as per the manufacturer's recommended dosage of 0.2 mg/kg/day for up to 5 days. Numerous reports have shown that lower, and even single doses are effective in lowering UA levels but prospective randomized studies comparing low doses have not been performed. OBJECTIVES: To prospectively determine the efficacy and safety of two single low doses of rasburicase in adult patients (pts) with acute leukemia and elevated plasma UA. METHODS: Eligible pts aged ≥ 18 years old with acute leukemia and UA ≥ 7.5 mg/dL were randomized to receive an initial single dose of rasburicase 1.5 mg (Arm A) or 3 mg (Arm B) on day 1 in an unblinded fashion. All pts received allopurinol 300 mg daily on days 1-6. RESULTS: Twenty-four pts (median age 69 years; 14 males and 10 females) were enrolled in this phase 2 study (12 on each arm). Twenty pts had acute myeloid leukemia while 3 had acute lymphoblastic leukemia, and 1 had acute promyelocytic leukemia. Median initial UA level was 9.8 mg/dL. Eighty-three percent of pts in both arms achieved UA < 7.5 mg/dL by 24 h after therapy. Five pts (21 %; 2 from Arm A and 3 from Arm B) required additional doses of rasburicase. The majority (23/24) of pts achieved UA goals after 1-2 doses of rasburicase. None had worsening renal function. Both doses were well tolerated, and no treatment related adverse events were reported. CONCLUSIONS: Single doses of rasburicase (as low as 1.5-3 mg) used in addition to allopurinol were well tolerated and highly efficacious (83 % response rate) in decreasing UA levels within 24 h of administration in adult acute leukemia pts with hyperuricemia.


Assuntos
Hiperuricemia/tratamento farmacológico , Hiperuricemia/etiologia , Leucemia Mieloide Aguda/complicações , Proteínas Recombinantes/administração & dosagem , Urato Oxidase/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Alopurinol/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Hiperuricemia/urina , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
9.
Arthritis Rheumatol ; 73(8): 1523-1532, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33750034

RESUMO

OBJECTIVE: Pegloticase is used for the treatment of severe gout, but its use is limited by immunogenicity. This study was undertaken to evaluate whether mycophenolate mofetil (MMF) prolongs the efficacy of pegloticase. METHODS: Participants were randomized 3:1 to receive 1,000 mg MMF twice daily or placebo for 14 weeks, starting 2 weeks before receiving pegloticase and continuing while receiving intravenous pegloticase 8 mg biweekly for 12 weeks. Participants then received pegloticase alone from week 12 to week 24. The primary end points were the proportion of patients who sustained a serum urate level of ≤6 mg/dl at 12 weeks and the rate of adverse events (AEs). Secondary end points included 24-week durability of serum urate level ≤6 mg/dl. Fisher's exact test and Wilcoxon's 2-sample test were used for analyses, along with Kaplan-Meier estimates and log rank tests. RESULTS: A total of 32 participants received ≥1 dose of pegloticase. Participants were predominantly men (88%), with a mean age of 55.2 years, mean gout duration of 13.4 years, and mean baseline serum urate level of 9.2 mg/dl. At 12 weeks, a serum urate level of ≤6 mg/dl was achieved in 19 (86%) of 22 participants in the MMF arm compared to 4 (40%) of 10 in the placebo arm (P = 0.01). At week 24, the serum urate level was ≤6 mg/dl in 68% of MMF-treated patients versus 30% of placebo-treated patients (P = 0.06), and rates of AEs were similar between groups, with more infusion reactions occurring in the placebo arm (30% versus 0%). CONCLUSION: Our findings indicate that MMF therapy with pegloticase is well tolerated and shows a clinically meaningful improvement in targeted serum urate level of ≤6 mg/dl at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Supressores da Gota/administração & dosagem , Gota/tratamento farmacológico , Ácido Micofenólico/administração & dosagem , Polietilenoglicóis/administração & dosagem , Urato Oxidase/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Gota/imunologia , Supressores da Gota/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/imunologia , Estudo de Prova de Conceito , Resultado do Tratamento , Urato Oxidase/imunologia
10.
BMJ Case Rep ; 14(3)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727299

RESUMO

We report a case of a 91-year-old Caucasian woman with a history of chronic lymphocytic leukaemia who developed acute hypoxic respiratory failure (AHRF) requiring intubation for less than 24 hours after receiving rasburicase. Laboratory workup was significant for methemoglobinemia and acute anaemia, and blood film demonstrated evidence of oxidative haemolysis with bite cells. The patient was given a presumptive diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency and was managed conservatively with successful resolution of AHRF and stabilisation of haemoglobin level. Seven days after admission, she passed away due to subsequent complications; hence, follow-up G6PD level could not be obtained. Haemolytic anaemia and methemoglobinemia in the setting of recent rasburicase administration should raise clinical suspicion for G6PD deficiency. In non-emergent cases, patients should be screened prior to receiving rasburicase regardless of risk factors. Because rasburicase is often needed emergently, patients at high risk of tumour lysis syndrome should be screened early for G6PD deficiency.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Metemoglobinemia , Idoso de 80 Anos ou mais , Feminino , Deficiência de Glucosefosfato Desidrogenase/complicações , Hemólise , Humanos , Metemoglobinemia/induzido quimicamente , Metemoglobinemia/diagnóstico , Metemoglobinemia/tratamento farmacológico , Urato Oxidase/efeitos adversos
11.
Asian Pac J Cancer Prev ; 22(2): 627-632, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33639683

RESUMO

OBJECTIVE: Management of hyperuricemia is crucial to controlling tumor lysis syndrome (TLS) during cancer therapy. Urate oxidase (UOX) that catalyzes the enzymatic oxidation of uric acid into allantoin, is effective in lowering plasma uric acid levels and controlling hyperuricemia. Recently, we developed a new recombinant conjugate variant of UOX therapeutic drug using PASylation technology. This study was designed to evaluate the stability, plasma half-life and immunogencity of PASylated UOX. METHODS: A recombinant variant of PASylated UOX from the Aspergillus flavus was manufactured using bioinformatics and experimental techniques. Ex vivo evaluation of stability of PASylated UOX was done in 50% human serum. For half-life test, recombinant PASylated UOX and rasburicase were administered at 1.5 mg/kg to 10 rats in two different groups and samples were collected after injection Production of antibodies against PASylated drug was also assayed. RESULTS: Residual activity of PASylated UOX in 50% human serum was higher than rasburicase and native UOX. Stability of PASylated UOX at 25°C and 37°C was also higher than rasburicase and native UOX. The PASylated half-life was ~32.1 hours, whereas half-life for rasburicase and native UOX was ~25.1 and ~22.8 hours, respectively. In immunogenicity examination, there is 33% and 36% decrease in the absorbance of native UOX and rasburicase, respectively when compared with that of PASylated UOX. CONCLUSION: Our data confirmed the efficacy and stability of PASylated UOX in comparison to the rasburicase. In summary, the results indicated that PASylated UOX drug is effective at lowering plasma uric acid levels with prolonged plasma half-life and decreased cost.
.


Assuntos
Hiperuricemia/tratamento farmacológico , Urato Oxidase/farmacologia , Animais , Estabilidade de Medicamentos , Meia-Vida , Humanos , Hiperuricemia/sangue , Ratos , Proteínas Recombinantes
12.
Semin Arthritis Rheum ; 51(2): 347-352, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33601190

RESUMO

INTRODUCTION: Pegloticase is a recombinant PEGylated uricase that converts relatively insoluble urate to highly water-soluble allantoin, which is readily excreted by the kidneys. It is the first and only biologic treatment indicated for refractory or uncontrolled gout. Clinical trials showed a 6-month pegloticase responder rate of 42%, with the non-responder rate largely being attributed to the development of high-titer anti-drug antibodies (ADAs) against pegloticase. Immunomodulation attenuates ADA formation to biologics in a number of autoimmune conditions, but their use with pegloticase for uncontrolled gout is less established. This systematic review examined published cases of refractory gout patients treated with immunomodulation in combination with pegloticase. METHODS: Published cases of immunomodulation with pegloticase were identified in a PubMed search and in abstract databases of major rheumatology society meetings (2012-2020). Duplicate and review articles were excluded, as were those that did not include cases of pegloticase use with immunomodulation. Cases with off-label pegloticase administration schedules were also excluded. Pegloticase response was defined according to each study's specified standard. RESULTS: Ten publications describing 82 cases of pegloticase use in the setting of immunomodulation were identified. Overall pegloticase response rate was 82.9%. Patients co-treated with an individual immunomodulator had the following response rates: methotrexate: 87.5% (35 of 40 patients), mycophenolate mofetil: 86.4% (19 of 22 patients vs. pegloticase monotherapy [placebo]: 40% [4 of 10 patients]), azathioprine: 63.6% (7 of 11 patients), and leflunomide: 66.7% (4 of 6 patients). A single patient was co-treated with cyclosporin and was a responder. The two patients treated with more than one immunomodulator were both responders. CONCLUSION: Published reports suggest that immunomodulation co-therapy has the potential to markedly improve pegloticase responder rates in patients with uncontrolled gout.


Assuntos
Supressores da Gota , Gota , Fatores Imunológicos , Polietilenoglicóis , Urato Oxidase , Azatioprina/uso terapêutico , Gota/tratamento farmacológico , Supressores da Gota/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Urato Oxidase/uso terapêutico , Ácido Úrico
13.
Biosens Bioelectron ; 179: 113082, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33601134

RESUMO

Uric acid analysis is extremely important for gout prognosis, diagnosis and treatment. Previous technologies either lack specificity or exhibit poor performance, and thus could not meet the need of Point-of-Care (POC) uric acid monitoring. Here we present for the first time, a novel electrochemical biosensor based on 3D Super-Aligned Carbon NanoTube (SACNT) array to facilitate POC uric acid monitoring. The working electrode of the biosensor is composed of an orderly 3D SACNT array immobilized with uricase through a precipitation and crosslinking procedure. Such biosensor possesses a higher enzyme density, significantly larger contact area with reactants and could maintain the intact SACNT structure and its excellent conductivity after modification. The developed 3D SACNT array electrochemical biosensor benefits from high specific surface area, high electro-catalytic activity and large contact area with analytes, and demonstrates high sensitivity of 518.8 µA/(mM⋅cm2), wide linear range of 100-1000 µM and low limit of detection of 1 µM for uric acid. Dynamic uric acid monitoring has been achieved using the presented biosensor. And the obtained results in serum samples had no significant difference compared with those obtained using the FDA-approved electrochemical analyzer (Paired T-test, p > 0.05). These demonstrated that the technology can potentially be applied in POC monitoring of other biomolecules to improve prognosis, diagnosis and treatment outcomes of metabolic diseases.


Assuntos
Técnicas Biossensoriais , Nanotubos de Carbono , Técnicas Eletroquímicas , Eletrodos , Sistemas Automatizados de Assistência Junto ao Leito , Urato Oxidase , Ácido Úrico
14.
Int J Biol Macromol ; 175: 30-39, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513422

RESUMO

A high serum uric acid (SUA) concentration is associated with hyperuricemia (HUA) and gout. In order to obtain long-acting therapeutic effect, correction of purine metabolism at genetic level is advantageous. For this purpose, we expressed three "human-like" urate oxidases in human hepatocytes (HL-7702) by lentivirus-mediated transduction. Enzymatic assay revealed that the recombinant urate oxidases expressed in HL-7702 cells were functionally active. Electron microscopy study showed that the recombinant enzymes were localized to peroxisome and formed distinct crystalloid core structures as in other mammal cells. Although similar rate of uric acid degradation was observed for all recombinant urate oxidases, HL-7702-pLVX-UOX83 cells and HL-7702-pLVX-UOX214/217 cells retained more cell viability compared with HL-7702-pLVX-UOXPBC at high uric acid level. This study provides a new direction for the treatment of gout and hyperuricemia.


Assuntos
Hepatócitos/metabolismo , Urato Oxidase/metabolismo , Proliferação de Células , Expressão Gênica , Gota/sangue , Gota/tratamento farmacológico , Células HEK293 , Hepatócitos/enzimologia , Humanos , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Microscopia Eletrônica/métodos , Proteínas Recombinantes/metabolismo , Urato Oxidase/genética , Ácido Úrico/sangue
15.
Clin Exp Rheumatol ; 39(5): 1085-1092, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33427618

RESUMO

OBJECTIVES: To determine factors associated with gout flares in subjects treated with pegloticase. METHODS: Gout flares from two randomised controlled trials comparing pegloticase (8 mg every 2 weeks [q2] or monthly [q4]) versus placebo were analysed. Responders had persistent urate lowering (<6mg/dL) whereas, non-responders had transient urate lowering during the 6-month RCTs. Gout flares (self-reported) were defined as acute joint pain and swelling requiring treatment. Gout flare prophylaxis (colchicine, 0.6 mg once or twice daily, or a non-steroidal anti-inflammatory drug) was initiated 1 week before the first infusion and continued throughout the study. Plasma urate at the time of flare and the change in urate preceding a flare were analysed. RESULTS: Mean flare rates increased with pegloticase versus placebo during the first 3 months followed by marked reductions during months 4-6. The increase in flares with pegloticase during the first 3 months was most evident (p=0.0006) and the decrease during the second 3 months was least marked (p=0.0006) in subjects receiving monthly pegloticase. Fluctuation in urate levels was highest in monthly responders (p=0.002) and was associated with flare occurrence. Multivariate linear regression analysis indicated the only variables significantly associated with flares were treatment group and absolute change in plasma urate before flares. CONCLUSIONS: Pegloticase treatment increased flares during the first 3 months of treatment in all groups when plasma urate was significantly lowered and was followed by a decline in months 4-6 in patients maintaining a low plasma urate. Flares associated with pegloticase treatment were associated with decreases and fluctuations in plasma urate levels.


Assuntos
Gota , Ácido Úrico , Doença Crônica , Gota/tratamento farmacológico , Supressores da Gota/uso terapêutico , Humanos , Polietilenoglicóis , Exacerbação dos Sintomas , Urato Oxidase
16.
Medicina (Kaunas) ; 57(1)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435164

RESUMO

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.


Assuntos
Hiperuricemia/tratamento farmacológico , Uricosúricos/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Acetamidas/uso terapêutico , Alopurinol/uso terapêutico , Benzobromarona/uso terapêutico , Doença Crônica , Medicina Baseada em Evidências , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Humanos , Naftalenos/uso terapêutico , Nitrilas/uso terapêutico , Fenilacetatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Probenecid/uso terapêutico , Propionatos/uso terapêutico , Piridinas/uso terapêutico , Tioglicolatos/uso terapêutico , Triazóis/uso terapêutico , Urato Oxidase/uso terapêutico
17.
J Pediatr Hematol Oncol ; 43(6): e886-e890, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33122582

RESUMO

Rasburicase is a recombinant urate oxidase enzyme indicated for tumor lysis syndrome, a potential life-threatening oncologic emergency that occurs most commonly during initial chemotherapy for hematological malignancies. As a result of the defects in the physiological antioxidant pathway, erythrocytes of patients with glucose-6-phosphate dehydrogenase deficiency are not protected against the oxidizing stress exerted by hydrogen peroxide generated with the administration of rasburicase. The authors report a 14-year-old patient, diagnosed with T-cell acute lymphoblastic leukemia, who developed methemoglobinemia and hemolytic anemia with low oxygen saturation after starting steroids, hyperhydratation, and rasburicase administration. The complications resolved with supportive therapy only.


Assuntos
Metemoglobinemia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Urato Oxidase/efeitos adversos , Adolescente , Anemia Hemolítica/induzido quimicamente , Anemia Hemolítica/diagnóstico , Humanos , Masculino , Metemoglobinemia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Urato Oxidase/uso terapêutico
18.
J Biochem ; 169(1): 15-23, 2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33002140

RESUMO

Urate oxidases (UOs) catalyze the cofactor-independent oxidation of uric acid, and an extensive water network in the active site has been suggested to play an essential role in the catalysis. For our present analysis of the structure and function of the water network, the crystal qualities of Bacillus sp. TB-90 urate oxidase were improved by controlled dehydration using the humid air and glue-coating method. After the dehydration, the P21212 crystals were transformed into the I222 space group, leading to an extension of the maximum resolution to 1.42 Å. The dehydration of the crystals revealed a significant change in the five-water-molecules' binding mode in the vicinity of the catalytic diad, indicating that these molecules are quasi-stable. The pH profile analysis of log(kcat) gave two pKa values: pKa1 at 6.07 ± 0.07 and pKa2 at 7.98 ± 0.13. The site-directed mutagenesis of K13, T73 and N276 involved in the formation of the active-site water network revealed that the activities of these mutant variants were significantly reduced. These structural and kinetic data suggest that the five quasi-stable water molecules play an essential role in the catalysis of the cofactor-independent urate oxidation by reducing the energy penalty for the substrate-binding or an on-off switching for the proton-relay rectification.


Assuntos
Bacillus/enzimologia , Proteínas de Bactérias/metabolismo , Urato Oxidase/metabolismo , Água/química , Substituição de Aminoácidos , Bacillus/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Sítios de Ligação , Catálise , Domínio Catalítico , Cristalografia por Raios X/métodos , Dessecação/métodos , Umidade , Cinética , Lisina/genética , Lisina/metabolismo , Mutagênese Sítio-Dirigida/métodos , Treonina/genética , Treonina/metabolismo , Urato Oxidase/química , Urato Oxidase/genética
19.
J Rheumatol ; 48(5): 767-774, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32934137

RESUMO

OBJECTIVE: To examine the efficacy and safety of pegloticase in combination with methotrexate (MTX) in patients with uncontrolled gout in an exploratory, open-label clinical trial (ClinicalTrials.gov: NCT03635957) prior to a randomized, controlled trial. METHODS: A multicenter, open-label efficacy and safety study of pegloticase with MTX co-treatment was conducted in patients with uncontrolled gout. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase treatment. The primary study outcome was the proportion of responders, defined as serum uric acid (sUA) < 6 mg/dL for ≥ 80% of the time during Month 6 (Weeks 20, 22, and 24). All analyses were performed on a modified intent-to-treat population, defined as patients who received ≥ 1 pegloticase infusion. RESULTS: Seventeen patients were screened and 14 patients (all men, average age 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL, and 12 of the 14 patients had visible tophi. At the 6-month timepoint, 11/14 (78.6%, 95% CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting protocol-defined treatment discontinuation rules (preinfusion sUA values > 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. No new safety concerns were identified. CONCLUSION: In this study, an increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase as compared to the previously reported 42% using pegloticase alone. These results support the need for a randomized study of MTX or placebo with pegloticase to validate these open-label findings.


Assuntos
Gota , Metotrexato , Adulto , Gota/tratamento farmacológico , Supressores da Gota/efeitos adversos , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Resultado do Tratamento , Urato Oxidase , Ácido Úrico
20.
Mod Rheumatol ; 31(4): 875-884, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32946311

RESUMO

METHODS: Baseline and follow-up DECTs were performed under a standard ULT protocol. Monthly dissolution rates were calculated by simple and compound methods. Correlations with average SU were compared and analyzed. Best-fit regression model was identified. MSU dissolution times were plotted against SU at different endpoints. RESULTS: In 29 tophaceous gout patients, MSU volume reduced from baseline 10.94 ± 10.59 cm3 to 2.87 ± 5.27 cm3 on follow-up (p = .00). Dissolution rate had a stronger correlation with SU if calculated by compound method (Pearson's correlation coefficient r= -0.77, p = .00) and was independent of baseline MSU load. The ensuing dissolution model was logarithmic and explained real-life scenarios. When SU > 0.43 mmol/l, dissolution time approached infinity. It improved to 10-19 months at SU = 0.24 mmol/l. When SU approximated zero (as with pegloticase), dissolution flattened and still took 4-8 months. CONCLUSION: MSU dissolution is better described as a logarithmic function of SU, which explains, predicts, and facilitates understanding of the dissolution process.


Assuntos
Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Urato Oxidase/uso terapêutico , Ácido Úrico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Solubilidade , Tomografia Computadorizada por Raios X/métodos , Ácido Úrico/metabolismo
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