Co-delivery of indomethacin and uricase as a new strategy for inflammatory diseases associated with high uric acid.

Uric acid is the final metabolite in humans. High level of uric acid chronically induces urate deposition, aggravates kidney damage, and concomitantly causes an increase in inflammatory factors. Alleviating acute inflammation and decreasing uric acid levels are the key points in the treatment of inflammatory diseases associated with high uric acid. However, a drug delivery system that combines anti-inflammatory and uric acid reduction functions at the same time remains a challenge to be settled. Here, we designed a nanocrystal-based co-delivery platform, IND Nplex, characterized by loading of indomethacin (IND) and uricase. Compared with free IND or uricase, IND Nplex possessed a better anti-inflammatory effect by restraining the release of inflammation-related factors in vitro. In addition, pharmacokinetic and biodistribution studies revealed that IND Nplex significantly prolonged the retention time in vivo and was more concentrated in the kidney. In acute gouty arthritis model rats, IND Nplex markedly relieved ankle joint swelling and mitigated synovial inflammation. In acute kidney injury model rats, IND Nplex indicated better biocompatibility and significant amelioration of renal fibrosis. Moreover, IND Nplex showed the effect of anti-inflammatory and improved renal function via determination of inflammatory factors and biochemical markers in the serum and kidney. In conclusion, these results indicate that IND Nplex exerts anti-inflammatory activity and uric acid-lowering effect and could become a promising candidate for the treatment of uric acid-related diseases.

Survey of Anaphylaxis during Rasburicase Re-Administration in Patients with Hematological Malignancies Using a Japanese Claims Database.

Management of tumor lysis syndrome (TLS) associated with cancer chemotherapy for malignant tumors is important because of its potentially fatal course. The use of rasburicase, a recombinant urate oxidase, is recommended for TLS; however, because rasburicase is an enzymatic drug, one should be cautious of anaphylaxis during administration. Using claims data in Japan, we investigated the rate of rasburicase re-administration and the occurrence of anaphylaxis during re-administration in patients with hematopoietic malignancies in a multicenter setting. Re-administration of rasburicase was defined as administration after an interval of 21 days from the first dose. Of 373 patients, 18 were re-administered rasburicase (re-administration rate: 4.8%). No patient developed anaphylaxis. The median number of days from the first to the last dose of rasburicase was 256.5 days (interquartile range: 138.8-455.8 days). The median daily dose was 7.5 mg (4.5-11.3 mg), and the median total dose was 33.8 mg (19.1-64.1 mg). This claims database analysis revealed that the re-administration rate of rasburicase was low in Japanese patients with hematopoietic malignancies, suggesting that rasburicase was being used appropriately, and that associated anaphylaxis was not observed.

Impact of pre-emptive rapid testing for glucose-6-phosphate dehydrogenase deficiency prior to rasburicase administration at a tertiary care centre: A retrospective study.

AIMS: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy in humans, can cause acute haemolysis resulting from exposure to certain medications, chemicals, infections and fava beans. Rasburicase, used to manage elevated uric acid levels in the oncologic emergency of tumour lysis syndrome, is one such drug. The US Food and Drug Administration (FDA) recommends testing of G6PD status prior to rasburicase administration for patients at higher risk for G6PD deficiency. METHODS: We performed a retrospective chart review of all oncology patients for whom a semi-quantitative biochemical test for detecting G6PD deficiency was performed prior to rasburicase administration over a 2.5-year period, in a large academic metropolitan hospital. RESULTS: We identified 16 out of 260 tested individuals as G6PD-deficient (6.1%), including six females. On average, test results were electronically available to health care providers within 4 hours of sample collection, with most results available within 2-3 hours. Four G6PD-deficient patients developed elevated uric acid levels. Two of the G6PD-deficient patients were treated with rasburicase, and subsequently developed haemolysis, which was appropriately managed. CONCLUSION: In summary, by providing information about G6PD status with a rapid turnaround time, we have taken a significant step towards personalized medicine in our institution. In spite of the test implementation, two out of four G6PD-deficient patients, who were no longer candidates for rasburicase use, still received the drug, highlighting the need for improved provider education.

Management of Hyperleukocytosis in Childhood Acute Leukemia Without Leukapheresis and Rasburicase Prophylaxis.

Indications of leukapheresis (LPh) and the prophylactic use of rasburicase in tumor lysis syndrome (TLS) of patients with acute leukemia with hyperleukocytosis are not clear. In this retrospective single-center pediatric study, the outcomes of patients with hyperleukocytosis were reviewed. There were 48 patients with acute lymphoblastic leukemia (ALL) and 13 patients with acute myeloblastic leukemia (AML). The treatment strategies included hyperhydration, allopurinol administration, strict monitoring, and early initiation of induction chemotherapy (CT). No patient underwent LPh because it was not available. Rasburicase was used only in 3 ALL patients with hyperuricemia when the drug was available. Laboratory and clinical TLS developed in 54.16% and 14.58% of patients with ALL, respectively. Laboratory and clinical TLS developed in 76.92% and 15.38% of patients with AML, respectively. No patient developed grade III to V TLS requiring dialysis. Thirteen patients (21.3%) had pulmonary leukostasis on admission, but recovered with CT and nasal oxygen. During the first 14 days of presentation, cerebral leukostasis/coagulopathy-related early death (ED) was 4.2% and 7.7% in patients with ALL and AML, respectively, and all of these patients had a white blood cell count ≥400,000/µL. There was also 1 infection-related death. Patients with hyperleukocytosis can be treated without LPh and liberal use of rasburicase. Renal failure is no longer a cause of ED. Intracranial hemorrhage is the main cause of ED, especially in patients already presenting with this complication. LPh may be performed in patients with leukostasis, if it is not possible to start induction CT early. When resources are limited, rasburicase should be administered in patients presenting with or developing hyperuricemia and/or renal dysfunction.

Fixed-Dose Recombinant Urate Oxidase in the Treatment of Paediatric Tumour Lysis Syndrome: A Regional Cancer Centre Experience.

BACKGROUND: Tumor lysis syndrome (TLS) is an oncologic emergency commonly seen in children with hemato-lymphoid malignancies. Recombinant urate oxidase (RUO) is used in both the prophylaxis and treatment of TLS. However, in resource-constrained countries, its role is mostly limited to the treatment of established TLS and data regarding the use of RUO and its outcome is sparse. OBJECTIVE: To describe the outcome of Pediatric TLS following the use of a fixed - dose of RUO. METHODS: A retrospective chart review of all children <15 years of age admitted in the Department of Paediatric Oncology, Kidwai Cancer Institute from April 2017 to July 2018 with TLS and treated with a single, fixed - dose (1.5 mg) RUO was undertaken. RESULTS: During the study period, 255 children with hemato-lymphoid malignancies were diagnosed to be at risk of developing TLS. Of these, only 22 (8.6%) children developed TLS and received RUO. Among those with TLS, 15 (68.2%) had Acute Lymphoblastic Leukemia (ALL) while 7 (31.8%) had Non - Hodgkin lymphoma (NHL). 91% (20/22) children had spontaneous TLS and the remainder developed therapy-related TLS. Median age at presentation was 8 years (IQR 5.25,1.75) with 4.5:1 male: female ratio. The mean urate level at admission was 19.12 mg/dl (+/- 8mg/dl) (Range: 10.7-34.5). 91% (20/22) children received RUO at less than 0.15 mg/kg and the median dose of RUO was 0.05 mg/kg (IQR 0.038-0.08). Of the 22 children with TLS, 2 children failed to achieve normal serum urate levels at 24 hours in response to a single fixed-dose of RUO and hence received an extra dose of RUO. Serum urate levels remarkably declined following RUO administration from 19.12 mg/dl (+/-8) to 8.2 mg/dl (+/-3.9), 3.99 mg/dl (+/-1.6) and 2.84 mg/dl (+/-1.3) at 12h, 24h and 48h respectively. AKI was present in 15 (68.2%) children. The median eGFR of the group at diagnosis was 49 ml/min/1.73m2 (IQR 26.3, 70). None of the children required hemodialysis. No significant adverse events occurred. CONCLUSION: Fixed-dose RUO can achieve rapid, adequate and sustained drop in serum urate levels in Paediatric TLS. It is a useful strategy for managing TLS in resource-constrained settings.

A phase 2 trial of single low doses of rasburicase for treatment of hyperuricemia in adult patients with acute leukemia.

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.

Multivalent Albumin-Neonatal Fc Receptor Interactions Mediate a Prominent Extension of the Serum Half-Life of a Therapeutic Protein.

Human serum albumin (HSA) has been used to extend the serum half-life of therapeutic proteins owing to its exceptionally long serum half-life via the neonatal Fc receptor (FcRn)-mediated recycling mechanism. In most cases, only one HSA molecule was conjugated to a therapeutic protein, leading to a limited extension of the serum half-life. In this study, we hypothesized that conjugation of multiple HSA molecules to a therapeutic protein significantly further extends the serum half-life via multivalent HSA-FcRn interactions. We chose urate oxidase (Uox), a tetrameric therapeutic protein used for the treatment of gout, as a model. In previous studies, only one HSA molecule was site-specifically conjugated to one Uox because of poor conjugation yield of the relatively slow bio-orthogonal chemistry, strain-promoted azide-alkyne cycloaddition (SPAAC). To increase the number of HSA molecules conjugated to one Uox, we employed the faster bio-orthogonal chemistry, inverse electron demand Diels-Alder reaction (IEDDA). We site-specifically introduced the phenylalanine analog with a fast-reacting tetrazine group (frTet) into position 174 of each subunit of Uox. We then achieved site-specific HSA conjugation to each subunit of Uox via IEDDA, generating Uox conjugated to four HSA molecules (Uox-HSA4), with a small portion of Uox conjugated to three HSA molecules (Uox-HSA3). We characterized Uox-HSA4 as well as Uox variants conjugated to one or two HSA molecules prepared via SPAAC (Uox-HSA1 or Uox-HSA2). The enzyme activity of all three Uox-HSA conjugates was comparable to that of unmodified Uox. We found out that an increase in HSA molecules conjugated to Uox (multiple albumin-conjugated therapeutic protein) enhanced FcRn binding and consequently prolonged the serum half-life in vivo. In particular, the conjugation of four HSA molecules to Uox led to a prominent extension of the serum half-life (over 21 h), which is about 16-fold longer than that of Uox-WT.

Reducing Immunogenicity of Pegloticase With Concomitant Use of Mycophenolate Mofetil in Patients With Refractory Gout: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

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.

Evaluation of the safety and efficacy of low-dose rasburicase in critically ill children with haematological malignancies.

Background The recommended dose of rasburicase is quite expensive, thus limiting its use. Whether a lower dose of rasburicase would be equally effective for critically ill children, who often have more complicated situations and a higher risk of hospital death, is still unknown. Objective To explore the safety and efficacy of low-dose rasburicase in critically ill children with haematological malignancies who are at high risk of tumour lysis syndrome. Setting A single-centre retrospective cohort study. Method Children with haematological malignancies who had a history of rasburicase exposure during an intensive care unit stay were enrolled. Patients were divided into two groups according to the initial dosage of rasburicase: the standard-dose group (> 0.1 mg/kg/day) and the low-dose group (≤ 0.1 mg/kg/day). The adverse events and short-term prognosis of the two groups were compared. Results Thirty-seven children were selected, 22 in the standard-dose group and 15 in the low-dose group. The most common tumour type was Burkitt's lymphoma (81%), followed by acute lymphoblastic leukaemia (11%). All patients were at high risk of tumour lysis syndrome, and 73% of them had 3 or more tumour lysis syndrome risk factors. The uric acid levels of 90% of patients with hyperuricaemia returned to the normal range within 12 h (100% in the standard-dose group and 75% in the low-dose group, P = 0.083). Eighty-four percent of patients presented serious complications, including tumour lysis syndrome (73%), acute kidney injury (59%), renal replacement treatment (24%), respiratory failure (24%), disseminated intravascular coagulation (16%) and heart failure (11%). There was no significant difference in the incidence of serious complications between the two groups. The overall 7-day and 28-day survival rates after intensive care unit admission were 86% and 84%, respectively. The average length of stay in the intensive care unit was 9.92 ± 5.13 days. Neither the short-term mortality nor the length of stay in the intensive care unit were significantly different between the two groups. Conclusion Low-dose rasburicase is effective and may be an acceptable choice for critically ill children with haematological malignancies.

Pegloticase hypersensitivity desensitisation: an outpatient, 3-bag, 12-step protocol.

Pegloticase is a highly effective treatment for refractory gouty arthropathy. Unfortunately, the medication is also highly immunogenic, leading to infusion reactions, loss of drug efficacy and anaphylaxis. Desensitisation, a procedure to tolerise a patient to a medication previously causing a hypersensitivity reaction, has been used successfully in oncology for chemotherapy treatment. The same principle can be applied to other specialties. Presented is a 48-year-old man who experienced multiple, severe infusion reactions to pegloticase administered for gouty arthropathy. A rapid desensitisation was performed using an outpatient, 3-bag, 12-step protocol, which allowed multiple additional pegloticase infusions to be performed without incident. This is the first reported case of a patient successfully desensitised after an infusion reaction to pegloticase. Though additional patients are needed to confirm these results, this represents a significant opportunity to recapture and continue pegloticase therapy in patients treated for refractory gouty arthropathy.

High-Dose IV Administration of Rasburicase Suppresses Anti-rasburicase Antibodies, Depletes Rasburicase-Specific Lymphocytes, and Upregulates Treg Cells.

Therapeutic proteins can be potent agents for treating serious diseases, but in many patients these proteins provoke antibody responses that blunt therapeutic efficacy. Intravenous administration of high doses of some proteins induces immune tolerance, but the mechanisms underlying this effect are poorly understood. As a model to study tolerance induction in mice, we used rasburicase, a commercial recombinant uricase used for the treatment of hyperuricemia. Intraperitoneal (i.p.) injection of rasburicase without or with alum adjuvants induced a clear anti-rasburicase antibody response, but intravenous (i.v.) injection did not. The lack of response to i.v. rasburicase was apparently due to active immune suppression since i.v.-treated mice showed blunted antibody and reduced T cell responses to subsequent i.p. injections of rasburicase. This blunted response was associated with a decrease in rasburicase-specific B cell and T cell responses and an increase in proportion of CD4+ FoxP3+ regulatory T cells (Treg) in the spleen. We examined the number of lymphocytes in peripheral blood after rasburicase i.v. injection. Rasburicase caused a transient reduction in B and T cells, but a robust and sustained depletion of rasburicase-specific B cells. Further experiments showed that rasburicase i.v. injection decreased the number of lymphocytes and was associated with apoptosis of both B cells and activated T cells and that the enhanced percentage of Treg cells was likely mediated by a macrophage-dependent pathway. Thus, our data suggest that apoptosis and depletion of antigen-specific B lymphocytes and upregulation of Treg cells may play important roles in the immune suppression induced by intravenous administration of a therapeutic protein.

Rasburicase in hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli: a report of nine cases.

BACKGROUND: Hyperuricemia might induce additional renal damage in children with hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS). A few case reports have shown rasburicase to be effective in decreasing serum uric acid (UA) and improving renal function. However, there is only one report on the use of rasburicase in a child with STEC-HUS, which shows satisfactory results. We describe here the safety and efficacy of rasburicase in nine additional cases. CASE-DIAGNOSIS/TREATMENT: Data from 9 children (5 females, median age 2 years) who received rasburicase were reviewed. At admission, 6 were dehydrated and 3 euvolemic. Dehydrated patients received saline solution and afterwards, as well as for those initially euvolemic, we aimed to keep a neutral fluid balance. Despite this, urine output did not increase. Baseline creatinine was 3.35 mg/dL (1.47-9.1) and UA 11.4 mg/dL (8.3-19.2). A single dose of rasburicase (0.2 mg/kg) was given 6-8 h after admission, which reduced UA levels to 1.8 mg/dL (0.3-5, p = 0.009) on the next day. However, renal parameters worsen and dialysis had to be initiated. Then, while still on dialysis, a UA rebound occurred in all cases reaching a peak of 8.9 mg/dL (4.5-13.8). Just after a steady increase in urine output, a sustained decline in UA levels concomitantly occurred with an improvement in renal function. At discharge, all patients reached normal UA levels. No side effects were recorded. CONCLUSIONS: Administration of rasburicase in children with STEC-HUS was safe but failed to provide any significant benefit despite fall in serum UA levels.

Pharmacokinetics of Polyethylene Glycol-Modified Canine Uricase Following Single and Multiple Intravenous Injections in Cynomolgus Monkeys.

BACKGROUND AND OBJECTIVE: Polyethylene glycol-modified canine uricase (PEG-UHC) prepared with a lower-molecular-weight (5 kDa) PEG is used to treat gout. This study investigated the comparative pharmacokinetics of single and multiple doses of PEG-UHC administered intravenously and a single dose of uricase (UHC) administered intravenously in cynomolgus monkeys. METHODS: A noncompartmental model was used to fit the plasma drug concentration-time curve and calculate the pharmacokinetic parameters of PEG-UHC, which were compared with those obtained for UHC at the equivalent dose (2 mg/kg). To study the pharmacokinetics after multiple dose administration, cynomolgus monkeys were administered five intravenous injections of PEG-UHC (0.5 mg/kg), with one injection performed every 15 days. RESULTS: The area under the curve (AUC) and the maximum plasma concentration (Cmax) of PEG-UHC were positively correlated with dose, whereas plasma half-life (t1/2) and clearance (CL) did not change significantly with increasing dose, suggesting that these pharmacokinetic characteristics are linear. Intravenous PEG-UHC exhibited an average t1/2 that was 125.79 times longer and an AUC0-t that was 64.45 times larger than the corresponding values for UHC at the same dose (2 mg/kg), while the CL of PEG-UHC was 1/72.73 times the CL of intravenous UHC. The plasma drug concentration reached a steady state after five injections, and the t1/2 values following the first and last drug administration did not differ significantly. CONCLUSION: Our data show that PEG-UHC is markedly superior to UHC in terms of duration of action, and that the pharmacokinetics of PEG-UHC in cynomolgus monkeys are linear. Sequential administration of PEG-UHC did not accelerate drug clearance. Our findings provide the basis for future clinical studies of PEG-UHC.

Bruton's tyrosine kinase inhibitors and the kidney: Focus on ibrutinib.

INTRODUCTION: Tumor lysis syndrome is an oncologic emergency resulting from rapid and massive tumor cell death that may lead to serious clinical complications including acute kidney injury and cardiac arrest. Tumor lysis syndrome most often occurs after the initiation of cytotoxic therapy in patients with high-grade lymphomas and acute lymphoblastic leukemia. CASE REPORT: We present a first case of patient with chemotherapy-resistant chronic lymphocytic leukemia and small lymphocytic lymphoma who developed tumor lysis syndrome upon treatment with ibrutinib (Imbruvica), a novel tyrosine kinase inhibitor. MANAGEMENT AND OUTCOME: The patient showed dramatic improvement in kidney function, uric acid and phosphorus after discontinuation of ibrutinib and a short course of rasburicase (recombinant urate oxidase), and two haemodialysis treatments. DISCUSSION: Clinicians should be aware of this serious side effect and closely monitor kidney function in patients treated with this oral kinase inhibitor.

Utilization patterns and clinical outcomes of rasburicase administration according to tumor risk stratification.

PURPOSE: Current guidelines for tumor lysis syndrome management recommend rasburicase for high-risk patients. Adherence to guidelines has not been well studied, and the correlation between uric acid reduction and clinically relevant outcomes, such as acute kidney injury, remains unclear. Our study aims to describe rasburicase utilization patterns and outcomes in cancer patients with varying risks for tumor lysis syndrome. METHODS: In this retrospective cohort study, we included cancer inpatients who received rasburicase for tumor lysis syndrome management at two affiliated academic hospitals from 2009 to 2015. Patients were classified by tumor lysis syndrome risk categories prior to drug administration. Primary outcomes included acute kidney injury incidence and renal recovery. Secondary outcomes included uric acid nadir, mortality, and hospital length-of-stay. RESULTS: Among 164 patients, 42 (26%) had high-, 63 (38%) had intermediate-, and 59 (36%) had low-risk for tumor lysis syndrome. A total of 94 patients (57%) had existing renal dysfunction prior to rasburicase use. This occurred more frequently in low- (68%) compared to intermediate- (57%) and high- (43%) risk patients (p = 0.044). A greater proportion of patients in the high-risk group (78%) had renal recovery when compared to the intermediate- (61%) or low- (45%) risk groups (p = 0.056). Despite a similar length of stay, the high-risk group had a significantly lower 30-day mortality (10%) when compared to intermediate- (25%) or low- (32%) risk groups (p = 0.029). CONCLUSIONS: Our results suggest that rasburicase may be frequently prescribed to treat hyperuricemia unrelated to tumor lysis syndrome in cancer patients. Improved education and adherence to guidelines may improve clinical and economic outcomes associated with rasburicase administration.

A retrospective analysis of tumor lysis syndrome management in a quaternary care hospital.

PURPOSE: Due to an increased use of rasburicase, the study's purpose was to evaluate both the management of tumor lysis syndrome and the utilization of rasburicase in the hospital system. Additionally, the efficacy of flat dose rasburicase in lowering uric acid levels was evaluated. Based on the study's findings, the investigators will evaluate the usefulness of implementing a tumor lysis syndrome order set. METHODS: This study evaluated patients from January 2013 through December 2016 for the rasburicase dose and the tumor lysis syndrome therapy administered. RESULTS: Overall, 251 patients were included: prophylactic rasburicase group (n = 125) vs. treatment rasburicase group (n = 126) and of rasburicase 3 mg (R3) group (n = 168) vs. 6 mg (R6) group (n = 83). The prophylactic rasburicase vs. treatment rasburicase group had a significantly lower rate of receiving a xanthine oxidase inhibitor (48.0% vs. 64.3%, p = 0.009), a phosphate binder (6.4% vs. 17.5%, p = 0.007) and an additional dose of rasburicase (20.8% vs. 41.3%, p = 0.001). Intravenous hydration was neither significantly different between the rasburicase groups (p = 0.399) nor between the two rasburicase dosing groups (p = 0.874). Between the rasburicase dosing groups, there was no significant difference in the rate of receiving a xanthine oxidase inhibitor (p = 0.521) or a phosphate binder (p = 0.390). R6 patients had a significantly greater reduction in uric acid change compared to R3 patients (median = -7.9 (-10.1, -5.5) vs. -4.3 (-6.0, -2.7), p < 0.0001). There was no significant difference in uric acid change between the prophylactic rasburicase and treatment rasburicase groups (p = 0.875). CONCLUSION: The study's findings justified the need to implement a tumor lysis syndrome order set. In the study population, utilizing a flat dosing method was effective for hyperuricemia.

Species and sex differences in the blood clearance and immunogenicity of PEGylated uricase: A comparative 26-week toxicity study in rats and monkeys.

Low response rates and high immunogenicity were observed after repeated injections of pegloticase (Krystexxa) into gout patients during clinical trials. However, related research had not been reported in preclinical animal experiments, which has limited the development of this drug. In this study, the toxicity of mPEG-UHC was studied in rats and monkeys over a 26-week period of repeated intravenous dosing. There were no obvious toxic reactions in the tested animals, with the exception of mPEG-UHC blood clearance and immunogenicity. After repeated injections of mPEG-UHC, rapid loss of uricolytic activity (RLA) was not detected in rats, whereas RLA was observed in 44.4% of drug-treated monkeys. In these monkeys, RLA was observed in 11.1% of males and 77.8% of females, and such incidences increased with higher dosing. High titres of anti-uricase IgG antibodies were associated with RLA but did not result in any toxicity. Remission and recurrence of RLA occurred in one female monkey in the high-dose group because of suppressed and altered immune responses in this animal. The predicted incidence of RLA after repeated injections of mPEG-UHC in gout patients may be lower than that of pegloticase. In this study, the no-observed-adverse-effect levels (NOAELs) of mPEG-UHC in rats and monkeys were 32.0 mg/kg and 20.0 mg/kg, respectively. Therefore, the results showed that rats and monkeys could tolerate long-term and high-dose administrations of mPEG-UHC, and mPEG-UHC blood clearance and immunogenicity showed obvious species and sex differences. These findings will provide valuable information to direct the clinical use of mPEG-UHC.

Rasburicase versus intravenous allopurinol for non-malignancy-associated acute hyperuricemia in paediatric cardiology patients.

OBJECTIVES: Limited data exist for management of hyperuricemia in non-oncologic patients, particularly in paediatric cardiac patients. Hyperuricemia is a risk factor for acute kidney injury and may prompt treatment in critically ill patients. The primary objective was to determine if rasburicase use was associated with greater probability normalisation of serum uric acid compared to allopurinol. Secondary outcomes included percent reduction in uric acid, changes in serum creatinine, and cost of therapy. DESIGN: A single-centre retrospective chart review. SETTING: A 20-bed quaternary cardiovascular ICU in a university-based paediatric hospital in California. PATIENTS: Patients admitted to cardiovascular ICU who received rasburicase or intravenous allopurinol between 2015 and 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from a cohort of 14 patients receiving rasburicase were compared to 7 patients receiving IV allopurinol. Patients who were administered rasburicase for hyperuricemia were more likely to have a post-treatment uric acid level less than 8 mg/dl as compared to IV allopurinol (100 versus 43%; p = 0.0058). Patients who received rasburicase had a greater absolute reduction in post-treatment day 1 uric acid (-9 mg/dl versus -1.9 mg/dl; p = 0.002). There were no differences in post-treatment day 3 or day 7 serum creatinine or time to normalisation of serum creatinine. The cost of therapy normalised to a 20 kg patient was greater in the allopurinol group ($18,720 versus $1928; p = 0.001). CONCLUSION: In a limited paediatric cardiac cohort, the use of rasburicase was associated with a greater reduction in uric acid levels and associated with a lower cost compared to IV allopurinol.

Co-delivery of therapeutic protein and catalase-mimic nanoparticle using a biocompatible nanocarrier for enhanced therapeutic effect.

Therapeutic proteins are indispensable in the treatment of various human diseases. Despite the many benefits of therapeutic proteins, they also exhibit diverse side effects. Therefore, reducing unwanted side effects of therapeutic proteins as well as enhancing their therapeutic efficacy are very important in developing therapeutic proteins. Urate oxidase (UOX) is a therapeutic enzyme that catalyzes the conversion of uric acid (UA) into a soluble metabolite, and it is used clinically for the treatment of hyperuricemia. Since UA degradation by UOX generates H2O2 (a cytotoxic side product), UOX was co-delivered with catalase-mimic nanoparticles (AuNPs) using biocompatible pluronic-based nanocarriers (NCs) to effectively reduce H2O2-associated toxicity in cultured cells and to enhance UA degradation efficiency in vivo. Simple temperature-dependent size changes of NCs allowed co-encapsulation of both UOX and AuNPs at a high loading efficiency without compromising critical properties, resulting in efficient modulation of a mixing ratio of UOX and AuNPs encapsulated in NCs. Co-localizing UOX and AuNPs in the NCs led to enhanced UA degradation and H2O2 removal in vitro, leading to a great reduction in H2O2-associated cytotoxicity compared with UOX alone or a free mixture of UOX and AuNPs. Furthermore, we demonstrated that co-delivery of UOX and AuNPs using NCs significantly improves in vivo UA degradation compared to simple co-injection of free UOX and AuNPs. More broadly, we showed that biocompatible pluronic-based nanocarriers can be used to deliver a target therapeutic protein along with its toxicity-eliminating agent in order to reduce side effects and enhance efficacy.