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Respiratory Medicine Case Reports 2019Rasburicase is a recombinant urate-oxidase enzyme and is a very important medication for tumor lysis syndrome. Methemoglobinemia and hemolysis are known side effects of...
Rasburicase is a recombinant urate-oxidase enzyme and is a very important medication for tumor lysis syndrome. Methemoglobinemia and hemolysis are known side effects of rasburicase that result from oxidative stress caused by hydrogen peroxide, a byproduct generated during the breakdown of uric acid to allantoin. Patients with G6PD deficiency have a decreased tolerance to oxidative stress and are therefore at a greater risk of hemolysis and methemoglobinemia with rasburicase. Our patient is a 56-year-old Caucasian male with a recent diagnosis of grade 2-3a non-Hodgkin's lymphoma who presented to our emergency department with shortness of breath and dark discoloration of urine. Patient was discharged 36 hours ago from our hospital after he was given a first course of R-CHOP regimen and a dose of rasburicase. On further evaluation, patient was found to have severe anemia with hemolytic picture, hyperkalemia and acute kidney injury. He also had a discrepancy of the transcutaneous saturation (75%) and the saturation in an arterial blood gas value (99%). His methemoglobin level was found to be 11.9%. We were aware that methylene blue is a contraindication in patients with G6PD deficiency but considering patient being Caucasian and low risk for it and his deteriorating respiratory condition, it was decided to offer the treatment and patient received 1 dose of methylene blue which failed to improve his methemoglobinemia. He was also given vitamin C and 8 units of packed red blood cell throughout his stay in the hospital. Patient's hospital course was complicated by ARDS needed to be on mechanical ventilation support for 4 days and acute renal failure secondary to pigment nephropathy and acute tubular necrosis which required a hemodialysis support. Even if rasburicase induced methemoglobinemia and hemolysis are not very common complications, clinicians who prescribe and follow patients should detect this serious complication early and manage it accordingly. Our case can be used as a reminder that patients should be followed closely and given the right instructions on discharge to treat these complications which are associated with severe consequences. It is also vital to assume a diagnosis of G6PD deficiency until proven otherwise in a patient who presents with rasburicase induced hemolysis and avoid administration of methylene blue even if the patient is from a low risk ethnicity for G6PD as in our patient.
PubMed: 30603605
DOI: 10.1016/j.rmcr.2018.12.011 -
The Canadian Journal of Hospital... 2019Rasburicase, a recombinant urate oxidase, is restricted in the Fraser Health Authority (FHA) to the "treatment of acute or at high risk of tumour lysis syndrome [TLS],...
BACKGROUND
Rasburicase, a recombinant urate oxidase, is restricted in the Fraser Health Authority (FHA) to the "treatment of acute or at high risk of tumour lysis syndrome [TLS], when other therapeutic options are not suitable". The manufacturer's recommended dosage is 0.2 mg/kg daily for up to 7 days. Given the high cost of this drug, several studies have investigated other strategies and found that a single dose, repeated as needed, is effective in reducing serum uric acid. However, there are currently no guidelines in FHA for the use of rasburicase, which may result in different prescribing practices within the health authority.
OBJECTIVES
To describe the prescribing of rasburicase in FHA, including indications and doses, and to report the uric acid-lowering effects of rasburicase and any clinical outcomes, such as dialysis or death.
METHODS
This retrospective descriptive chart review included adult patients receiving care in FHA for whom rasburicase was prescribed between June 1, 2010, and November 30, 2016. Descriptive statistics were used to summarize patient characteristics and results.
RESULTS
The prescribing practices for rasburicase in this health authority were largely inconsistent, but the most common dose administered was 3 mg (8/12 [67%] among those receiving rasburicase for prophylaxis and 9/32 [28%] among those receiving rasburicase for treatment; combined total 17/44 or 39%). Regardless of dose, rasburicase reduced serum uric acid levels to less than 476 μmol/L and decreased the risk of TLS.
CONCLUSIONS
Having a uniform approach-involving a single dose that can be repeated as needed-for prevention and treatment of elevated serum uric acid levels could result in sufficient reduction of uric acid levels with fewer doses and lower cost. The results of this study support the need for a resource in FHA to guide and standardize the use of rasburicase.
PubMed: 31452543
DOI: No ID Found -
The Cochrane Database of Systematic... Jun 2010Tumor lysis syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. Preliminary reports suggest that urate oxidase is highly... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tumor lysis syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. Preliminary reports suggest that urate oxidase is highly effective in reducing serum uric acid. It is uncertain whether high quality evidence exists to support its routine use in children with malignancies.
OBJECTIVES
We aimed to determine the effectiveness and safety of urate oxidase in the prevention and treatment of TLS in children with malignancies.
SEARCH STRATEGY
We performed a comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 2, 2009), MEDLINE (1966 to 2009), EMBASE (1980 to 2009) and CINAHL (1982 to 2009).
SELECTION CRITERIA
Randomized controlled trials (RCT) and controlled clinical trials (CCT) evaluating urate oxidase for the prevention or treatment of TLS in children under 18 years with any malignancy.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted trial data and assessed individual trial quality. We used relative risk (RR) for binary data and mean difference (MD) for continuous data.
MAIN RESULTS
We included five trials, involved 336 patients in the treatment groups and 458 patients in the control groups. One RCT and three CCTs compared urate oxidase and allopurinol. Two trials tested Uricozyme and two tested rasburicase for the prevention of TLS. The RCT showed no significant difference in mortality or renal failure between the treatment and the control groups. The frequency of normalization of uric acid (RR 19.09, 95% CI 1.28 to 285.41) and area under curve of uric acid (MD -201, 95% CI to -258.05 to -143.95) were significantly better in the treatment group. One patient developed hemolysis. One CCT reported significantly lower mortality due to TLS (RR 0.05, 95% CI 0.00 to 0.89) and lower incidence of renal failure (RR 0.13, 95% CI 0.05 to 0.35) in the treatment group. Another CCT found significantly lower uric acid in the treatment group at 72 hours (MD -98.33, 95% CI -170.66 to -26) and 168 hours (MD -103.67, 95% CI -179.00 to -28.34). All included trials are highly susceptible to biases.Another included RCT with 30 patients compared different doses of rasburicase (0.2 mg/kg versus 0.15 mg/kg), which demonstrated similar efficacy in the reduction of uric acid. Adverse events occurred in 20% of patients, including hemolysis, hypersensitivity and anemia.
AUTHORS' CONCLUSIONS
Although urate oxidase might be effective in reducing serum uric acid, it is still unclear whether this translates into a reduction in mortality or renal failure. Clinicians should weigh the potential benefits of reducing uric acid and uncertain benefits of preventing renal failure or mortality from TLS against the potential risk of adverse effects.
Topics: Allopurinol; Antimetabolites; Child; Controlled Clinical Trials as Topic; Humans; Neoplasms; Randomized Controlled Trials as Topic; Renal Insufficiency; Tumor Lysis Syndrome; Urate Oxidase; Uric Acid
PubMed: 20556770
DOI: 10.1002/14651858.CD006945.pub2 -
International Journal of Medical... Mar 2007Hyperuricemia is a feature of several pathologies and requires an appropriate and often early treatment, owing to the severe consequences that it may cause. A rapid and... (Review)
Review
Hyperuricemia is a feature of several pathologies and requires an appropriate and often early treatment, owing to the severe consequences that it may cause. A rapid and massive raise of uric acid, during tumor lysis syndrome (TLS), and also a lower and chronic hyperuricemia, as in gout, mainly damage the kidney. To prevent or treat these consequences, a new therapeutic option is represented by rasburicase, a recombinant form of an enzyme, urate oxidase. This enzyme converts hypoxanthine and xanthine into allantoin, a more soluble molecule, easily cleared by kidney. The several types of urate oxidase have followed each other, with progressive reduction of adverse reactions. The most important among them are allergenicity and the development of antibodies which compromise their effectiveness. Nevertheless, a limit of rasburicase's use remains its cost, which obliges to a judicious choice to prevent TLS in high risk patients with cancer and in case of allergy or impossibility to take allopurinol orally both in TLS and in gout. A large body of evidence confirms the efficacy and safety of rasburicase, even in comparison to the standard drugs used in the aforementioned pathologies.
Topics: Gout; Gout Suppressants; Humans; Hyperuricemia; Tumor Lysis Syndrome; Urate Oxidase; Uric Acid
PubMed: 17396159
DOI: 10.7150/ijms.4.83 -
Kidney & Blood Pressure Research 2018Current urate-lowering therapy (ULT) includes three direct acting drugs (allopurinol, febuxostat, Rasburicase) and at least four 'indirect' drugs with other important... (Review)
Review
Current urate-lowering therapy (ULT) includes three direct acting drugs (allopurinol, febuxostat, Rasburicase) and at least four 'indirect' drugs with other important targets (canagliflozin, losartan, fenofibrate and sevelamer). Moreover, the alcalinization of urines using bicarbonate can be used to dissolve urate crystals and the clinician may discontinue several drugs are known to increase serum levels of uric acid, such as diuretics, aspirin, cyclosporine, theophylline, mycophenolate and ACE inhibitors. While there is a consensus to start ULT in cases of symptomatic hyperuricemia (gout, urate-nephrolithiasis), the very frequent conditions of asymptomatic hyperuricemia remains a major conundrum. The effect of asymptomatic hyperuricemia on kidney function has had fluctuating positions over decades. The conflicting results might indicate: (i) the presence of counterbalancing positive and negative effects on kidney function of both serum uric acid and urate-lowering agents, (ii) the presence of a subpopulation of patients, as yet unidentified, which could truly benefit from a urate-lowering therapy. Therefore, today the treatment of asymptomatic hyperuricemia is not recommended nor excluded by current guidelines. Here we suggest that a possible guide for the treatment of asymptomatic hyperuricemia might be the presence of urate crystals in the urine sediment and/or signs of asymptomatic articular damage by urates, identified by musculo-skeletal ultrasound. Moreover, a watchful analysis of the trend in creatinine/eGFR, proteinuria or urate levels might also guide the clinician. Initiation of ULT and follow-up in cases of asymptomatic hyperuricemia should consider urine sediment analysis, musculoskeletal ultrasound and trends in creatinine, proteinuria and serum urate levels.
Topics: Antimetabolites; Humans; Hyperuricemia; Musculoskeletal System; Ultrasonography; Uric Acid; Urinalysis
PubMed: 29689561
DOI: 10.1159/000489145 -
Gynecologic Oncology Reports Nov 2019To describe the incidence, treatment and outcomes associated with tumor lysis syndrome (TLS) in women with gynecologic cancer (GOC). (Review)
Review
OBJECTIVES
To describe the incidence, treatment and outcomes associated with tumor lysis syndrome (TLS) in women with gynecologic cancer (GOC).
METHODS
A retrospective multi-institutional review of TLS associated with GOC. Women presenting with an elevated serum uric acid managed with intravenous (IV) rasburicase were included. Descriptive statistics of patient demographics, clinical findings, and outcome data was completed.
RESULTS
From two large academic institutions N = 18 patients were found to meet inclusion criteria from 2008 to 2018, reflecting an approximate 5% incidence of clinically treated TLS associated with GOC in our cohort. Median age was 60 years, a majority were Caucasian (n = 11, 61.1%), median BMI was 36.2. TLS was associated with a high-grade GOC in n = 17 (94.4%) cases. TLS was commonly diagnosed with a new GOC (n = 12, 70.6%) and following receipt of chemotherapy in n = 9 (50.0%) cases. Six (66.7%) patients were treated with paclitaxel or combination, five (55.5%) with a platinum or combination, and two (22.2%) with a CD47 inhibitor. Chief complaints included electrolyte and renal abnormalities (n = 11, 73.3%). Peak serum uric acid, potassium, creatinine and phosphorus levels were 14.1 mg/dL, 5.7 mEq/L, 5.1 mg/dL, and 6.8 mg/dL, respectively. Nine patients received hospice during their admission with 3 (20%) deaths occurring as inpatients. There were 12 deaths with median OS of 16 d (range: 2-87 d).
CONCLUSIONS
Though rare, TLS can be associated with GOC. Early recognition of presenting symptoms, laboratory findings and expedited treatment may help with electrolyte recovery; however, TLS associated with GOC may herald a rapidly deteriorating state with significant associated mortality.
PubMed: 31788528
DOI: 10.1016/j.gore.2019.100514 -
Physiological Reports Sep 2021We hypothesized acute moderate and drastic reductions in uric acid concentration exert different effects on arterial function in healthy normotensive and hypertensive... (Randomized Controlled Trial)
Randomized Controlled Trial
We hypothesized acute moderate and drastic reductions in uric acid concentration exert different effects on arterial function in healthy normotensive and hypertensive adults. Thirty-six adults (aged 58 [55;63] years) with or without primary hypertension participated in a three-way, randomized, double-blind, crossover study in which [placebo] and [febuxostat] and [febuxostat and rasburicase] were administered. Febuxostat and rasburicase reduce the uric acid concentration by xanthine oxidoreductase inhibition and uric acid degradation into allantoin, respectively. Endothelial function was assessed in response to acetylcholine, sodium nitroprusside, heating (with and without nitric oxide synthase inhibition) using a laser Doppler imager. Arterial stiffness was determined by applanation tonometry, together with blood pressure, renin-angiotensin system activity, oxidative stress, and inflammation. Uric acid concentration was 5.1 [4.1;5.9], 1.9 [1.2;2.2] and 0.2 [0.2;0.3] mg/dL with [placebo], [febuxostat] and [febuxostat-rasburicase] treatments, respectively (p < 0.0001). Febuxostat improved endothelial response to heat particularly when nitric oxide synthase was inhibited (p < 0.05) and reduced diastolic and mean arterial pressure (p = 0.008 and 0.02, respectively). The augmentation index decreased with febuxostat (ANOVA p < 0.04). Myeloperoxidase activity profoundly decreased with febuxostat combined with rasburicase (p < 0.0001). When uric acid dropped, plasmatic antioxidant capacity markedly decreased, while superoxide dismutase activity increased (p < 0.0001). Other inflammatory and oxidant markers did not differ. Acute moderate hypouricemia encompasses minor improvements in endothelial function, blood pressure, and arterial stiffness. Clinical Trial Registration: NCT03395977, https://clinicaltrials.gov/ct2/show/NCT03395977.
Topics: Adult; Aged; Blood Pressure; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Febuxostat; Female; Forearm; Gout Suppressants; Humans; Laser-Doppler Flowmetry; Male; Middle Aged; Oxidative Stress; Uric Acid; Vascular Stiffness
PubMed: 34435469
DOI: 10.14814/phy2.15018 -
British Journal of Clinical Pharmacology Feb 2021The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre-emptive genetic tests are now routinely... (Review)
Review
The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre-emptive genetic tests are now routinely undertaken prior to anticancer drug administration. Many of these gene-drug interactions are the fruits of candidate gene and genome-wide association studies, which have largely focused on common genetic variants (allele frequency>1%). Examples where there is clinical utility include genotyping or phenotyping for G6PD to prevent rasburicase-induced RBC haemolysis, and TPMT to prevent thiopurine-induced bone marrow suppression. Other associations such as CYP2D6 status in determining the efficacy of tamoxifen are more controversial because of contradictory evidence from different sources, which has led to variability in the implementation of testing. As genomic technology becomes ever cheaper and more accessible, we must look to the additional data our genome can provide to explain interindividual variability in anticancer drug response. Clearly genes do not act on their own and it is therefore important to investigate genetic factors in conjunction with clinical factors, interacting concomitant drug therapies and other factors such as the microbiome, which can all affect drug disposition. Taking account of all of these factors, in conjunction with the somatic genome, is more likely to provide better predictive accuracy in determining anticancer drug response, both efficacy and safety. This review summarises the existing knowledge related to the pharmacogenomics of anticancer drugs and discusses areas of opportunity for further advances in personalisation of therapy in order to improve both drug safety and efficacy.
Topics: Antineoplastic Agents; Genome-Wide Association Study; Humans; Pharmaceutical Preparations; Pharmacogenetics; Tamoxifen
PubMed: 32501544
DOI: 10.1111/bcp.14407 -
ACS Omega Dec 2022Recombinant urate oxidase (UOX, E.C.1.7.3.3) is an important therapeutic enzyme used in preventing and treating chemotherapy-induced hyperuricemia and severe gout....
Recombinant urate oxidase (UOX, E.C.1.7.3.3) is an important therapeutic enzyme used in preventing and treating chemotherapy-induced hyperuricemia and severe gout. However, UOX use is limited due to the poor stability and short plasma half-life. To solve this problem, we designed three PASylated variants of UOX with different PAS sequences at the C- or N-terminus. The genes of native and PASylated variants (UOX-PAS, PAS-UOX, and UOX-PAS) were designed and produced in strain BL21 (DE3). The expressed recombinant native and PASylated enzymes were compared in terms of biophysical properties, kinetics parameters, and pharmacokinetics behavior using standard methods. PASylation of UOX with PAS polymer caused a 1.24-fold reduction in to 52.61 μM, and a 3.87-fold increase in / for uric acid compared to the native variant. UOX-PAS retained its activity in different temperatures (20-55 °C); however, other variants lost nearly 50% of their original activity at 55 °C. UOX-PAS exhibited a 1.78-fold increase in hydrodynamic radius and a 1.64-fold larger apparent molecular size in comparison to the native UOX. Circular dichroism (CD) spectroscopy demonstrated that the addition of the PAS tag does not change the secondary structure of the fusion enzyme. The tryptophan fluorescence emission spectra for PASylated enzymes showed a significant modification in the conformational state of UOX by the PAS polymer presence. UOX-PAS retained 89.0% of the original activity following 72 h incubation in the presence of plasma at 37 °C. However, only about 61.0%, 57.0%, 50.0%, and 52.0% of activity from PAS-UOX, UOX-PAS, native UOX, and rasburicase (Fasturtec, Italy) remained, respectively, at the identical time. UOX-PAS had an increased biological half-life (8.21 h) when compared with the rasburicase (3.12 h) and native UOX (2.87 h) after being injected into a rat. Having considering everything, our results suggest that the UOX-PAS, an UOX fused with a C-terminally 100 amino acid PAS-residue, is a proper candidate with enhanced biological activity and extended plasma half-life for clinical therapy in patients suffering from hyperuricemia.
PubMed: 36570261
DOI: 10.1021/acsomega.2c04071