Rasburicase Effectively Lowers Serum Uric Acid Levels in High Risk, Poor Performance Status Patients with Hematologic Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4012-4012
Author(s):  
Doris Ponce ◽  
Delong Liu ◽  
Muhammad Rasul ◽  
Nasir Ahmed ◽  
Marie Dimicco ◽  
...  
Keyword(s):  
Renal Failure ◽  
Uric Acid ◽  
High Risk ◽  
Serum Uric Acid ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Urate Oxidase ◽  
Phase Iii ◽  
Poor Performance Status ◽  
High Dose

Abstract Tumor lysis remains a significant cause of morbidity and mortality in patients with highly proliferative hematologic malignancies. Traditionally, intravenous hydration and oral allopurinol have been the mainstays of therapy. However in some patients, hyperuricemia and renal failure still occur. The resultant renal failure precludes the administration of full doses of chemotherapy and results in a poor treatment outcome. Recently we participated in a large phase III randomized trial comparing rasburicase with standard allopurinol therapy. Rasburicase is a recombinant urate oxidase that effectively reduces serum uric acid due to conversion of uric acid into allantoin, a readily excretable and soluble substance. The results of that study are reported in a separate abstract. However while the study was open, we treated 12 extremely high risk, newly diagnosed hematologic malignancy patients who were ineligible for the study with commercially available rasburicase off study. The reasons for study ineligibility were ECOG Performance Status 4 and/or expected survival of less than one month. Other baseline characteristics: Diagnosis: Burkitts ALL: 3, AML: 7, CML-BP: 1, T-ALL: 1; Age: 64 (27–85), Sex: 6M/6F; WBC: 58,000/mm3 (1.6- 245,000); LDH: 2201 U/l (1068- >2500); # of preexisting comorbid medical conditions: 4 (0–7); chemotherapy: hyper-CVAD: 4, standard ara-c based rx: 5, high dose ara-C based rx: 3. Nine patients received one dose of rasburicase (0.2 mg/kg IV), 3 patients required a second dose. The median uric acid levels were: pretreatment : 9.2 mg/dl (2.8–28.6), at 24 hours: <0.2 (0.2–7.5) and at 48 hours: <0.2 (<0.2–4.9). All patients achieved normal serum uric acid level by day 2. The median baseline creatinine was 2.6 mg/dl (0.7 – 5.6); by day seven 10 patients had a serum creatinine less than 2 mg/dl (day 7 median creatinine 0.9, range 0.4–5.5). Four patients achieved CR to chemotherapy, 5 had refractory disease and 3 had induction death. Administration of rasburicase in this extremely high risk group of patients resulted in a rapid decrease in serum uric acid levels. In many patients this allowed for preservation of or improvement in renal function and administration of chemotherapy. Although some patients had a poor outcome due to the aggressive nature of their underlying disease, 4 of 12 patients (33%) attained CR and were able to receive subsequent cycles of intensive chemotherapy without incident.

Rasburicase Improves Renal Function and Uric Acid Nephropathy in Patients Developing Acute Renal Failure after Conditioning for Hematopoetic Stem Cell Transplant (HSCT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1142-1142
Author(s):  
Donovan Strader ◽  
Michael S. Oholendt ◽  
Uday Popat ◽  
George Carrum ◽  
Helen E. Heslop
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Acute Renal Failure ◽  
Uric Acid ◽  
Single Dose ◽  
Urate Oxidase ◽  
High Dose ◽  
Renal Tubules ◽  
Cell Transplant ◽  
Uric Acid Nephropathy

Abstract Significant reduction in renal function secondary to protein deposition in the renal tubules is a common occurrence among patients with plasma cell dyscrasias such as Multiple Myeloma (MM) and Amyloidosis undergoing HSCT. Conditioning chemotherapy and uric acid release following cellular lysis may worsen already compromised renal function, leading to acute renal failure. Rasburicase, a recombinant urate oxidase enzyme, has been approved by the U.S. Food and Drug Administration for the treatment and prevention of hyperuricemia associated with tumor lysis syndrome in pediatric patients with leukemia, lymphoma, and solid tumor malignancies undergoing chemotherapy. We hypothesized that prompt treatment of hyperuricemia with rasburicase may prevent uric acid nephropathy and improve renal function, obviating the need for dialysis and improving the eventual outcome. Six adults, four with MM and two with amyloidosis, with rising uric acid levels after high dose Melphalan (200mg/m2) were given a single dose of rasburicase (0.15 mg/kg). At baseline, all patients had rising serum creatinine [mean: 2.1 mg/dL (range: 0.9–4.5 mg/dL)], rising BUN [mean: 27.6 mg/dL (range: 1.3–70 mg/dL)], and declining creatinine clearance (CrCL) [mean: 50.5 ml/min (range: 16–75 ml/min)]. After one dose of rasburicase, renal function significantly improved according to CrCL at 48 hours [mean: 55.2 ml/min (range: 17–82 ml/min)] and continued to improve at five days [mean: 68.2 ml/min (range: 18–109 mg/dL)]. Baseline uric acid was elevated [mean: 8.61 mg/dL (range: 7–9.9 mg/dL)] and improved 24 hours after treatment with rasburicase [mean: 0.2 mg/dL (range: 0–0.6 mg/dL)]. None of the patients required renal replacement therapy. There were no serious adverse events associated with rasburicase therapy. We therefore conclude that a single dose of rasburicase is promising in improving deteriorating renal function post high dose chemotherapy in patients with compromised renal function; further controlled studies are warranted.

Fludarabine Melphalan and Alemtuzumab (Campath) Conditioning for Pts with High Risk Myeloid Malignancies. High Cure Rate for Pts with Low Leukemia Burden.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2321-2321 ◽  
Author(s):  
Koen W. van Besien ◽  
Andrew Artz ◽  
Sonali Smith ◽  
Elizabeth Rich ◽  
Lucy Godley ◽  
...  
Keyword(s):  
High Risk ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Hematologic Malignancies ◽  
High Dose ◽  
Long Term Outcome ◽  
Myeloid Malignancies ◽  
Low Incidence ◽  
One Year

Abstract Fludarabine melphalan conditioning has been used widely for conditioning of pts with hematologic malignancies. When combined with in vivo alemtuzumab, this regimen leads to reliable engraftment, minimal acute and chronic GVHD, and low early transplant-related mortality (TRM). Between 2002 and 2004, we conducted a prospective study in hematologic malignancies. Here we report outcomes in 55 patients with high-risk myeloid malignancies. Median age was 54 (range 17–71); 17 were 60 and older. 28 had HLA-identical related donors, 23 had MUD donors, and 4 had 1 Ag-MM related donors. 32 pts had high leukemia burden at transplant (24 active AML, 6 MDS with >5% blasts, 1 CML-BC, 1 myelofibrosis in transformation). 23 pts had low leukemia burden at transplant (4 AML in CR1 with adverse cytogenetics, 2 AML CR1 with WBC>100K, 1 AML CR1 requiring 2 inductions, 6 AML CR2, 1 AML CR3, 4 MDS <5% blasts, 2 CML-CP gleevec refractory, 1 CML-CP gleevec intolerant, 1 myelofibrosis, 1 PNH). ECOG performance status (PS) was > 0 in 20 pts. Many had other high risk features including 15 with prior transplant and 10 with secondary leukemia. Conditioning consisted of fludarabine-melphalan-alemtuzumab (as per Smith, Blood 2002, abstract 5292), with tacrolimus for GVHD prophylaxis until day 100. Stringent CMV prophylaxis with high dose valacyclovir was given for 180 days. There were two early graft rejections (both from1 Ag-MM related donors) and both pts died of aplasia. There were also 2 deaths during conditioning. Including these 4 pts, cumulative day 100 TRM is 17% (95% CI 7–27). Median follow-up for survivors is 14 months (range 2–30). Estimated one year survival is 53% (95% CI 39–67) and one year PFS is 44% (95% CI 30–68). Donor type did not affect survival. Age > 55 (HR 2; p= 0.04), PS > 0 (HR 2.4; p= 0.001) and high leukemia burden (HR 7.7; p=0.0001) were associated with decreased survival in univariate analysis. 20 of 23 pts with low leukemia burden remain alive, 18 in ongoing remission. By contrast, one year survival for pts with high leukemia burden is 35 % (figure). Only 1 case of grade III–IV acute GVHD was observed and extensive chronic GVHD occurred in 3 pts. CMV reactivation was common, but documented CMV pneumonia occurred in only one patient. Fludarabine melphalan alemtuzumab conditioning results in excellent long-term outcome for patients with high-risk myeloid malignancies and low leukemia burden, with a very low incidence of acute and chronic GVHD. In these disorders, GVHD is not a prerequisite for achievement of durable CR. For pts with high leukemia burden, therapy provided mainly palliative responses with a low incidence of GVHD. Further improvements are needed to reduce recurrence rate for pts with high leukemia burden. Figure Figure

Superiority of Rasburicase Versus Allopurinol on Serum Uric Acid Control in Adult Patients with Hematological Malignancies at Risk of Developing Tumor Lysis Syndrome : Results of a Randomized Comparative Phase III Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 919-919 ◽  
Author(s):  
Jorge Cortes ◽  
Karen Seiter ◽  
Richard Thomas Maziarz ◽  
Meir Wetzler ◽  
Michael Craig ◽  
...  
Keyword(s):  
At Risk ◽  
Uric Acid ◽  
Adverse Events ◽  
Serum Uric Acid ◽  
Hematological Malignancies ◽  
Tumor Lysis Syndrome ◽  
Urate Oxidase ◽  
Phase Iii ◽  
Tumor Lysis ◽  
Phase Iii Study

Abstract Tumor lysis syndrome (TLS) is a potentially lethal metabolic complication of chemotherapy or cytolytic antibody therapy usually seen in patients with hematologic malignancies, especially those malignancies with a high proliferative rate, large cellular burden and/or sensitivity to chemotherapy. The prevention and management of TLS includes hydration and reduction of serum uric acid (SUA) levels. Although Allopurinol (ALLO) has had longstanding use for TLS prophylaxis, its efficacy in controlling SUA is limited, especially due of its lack of action on pre-existing hyperuricemia. Rasburicase (RAS), a recombinant urate oxidase, effectively reduces SUA due to conversion of UA into allantoin, a readily excretable and soluble substance. RAS has significant activity in the initial management of TLS-associated acute hyperuricemia in pediatric populations, and is currently indicated in the US for this condition in children and adolescents. A prospective, randomized, controlled phase III study was conducted in adult pts to compare the efficacy in SUA control of RAS (0.20 mg/kg/d, IV) days 1–5, versus RAS+ALLO (RAS 0.20 mg/kg/d, IV days 1–3 plus oral ALLO 300 mg/day days 3–5) versus ALLO alone (300 mg/d) days 1–5. 280 pts (275 evaluable) with hematological malignancies at high or potential risk for TLS were enrolled. 92 pts received RAS, 92 pts received RAS+ALLO, and 91 received ALLO. Treatment arms were well balanced in terms of demographics, baseline characteristics, TLS risk, and percentage of pts with baseline hyperuricemia. The SUA response rate - defined as normalization of SUA (≤ 7.5mg/dl) at days 3–7 was 87.0% in the RAS arm, 78.3% in the RAS+ALLO arm and 65.9% in the ALLO arm. RAS was superior over ALLO (p=0.0009) in the overall study population as well as in pts at high risk TLS (89.0% vs. 62.8%, p=0.0012), and in pts with baseline hyperuricemia (89.5% vs. 52.9%, p=0.0151). The time to control SUA in hyperuricemic pts was 4.1 h in the RAS arm and 27 h in the ALLO arm. The mean SUA area under the curve (AUC) results indicated that there was an 8.4-fold increase in UA exposure in the ALLO arm compared to the RAS arm. There were no significant differences in the incidence or severity of adverse events, serious adverse events or deaths. The majority of RAS and/or ALLO-related adverse events were grade 1 and 2, and most of these events were hypersensitivity-related reactions. No cases of anaphylaxis, methemoglobinemia or hemolysis were observed with RAS treatment. In conclusion, RAS is superior to ALLO in normalization of SUA, with a faster effect, in adult pts at risk for TLS. RAS alone or followed by ALLO are two valid options for this patient population.

Effectiveness of a Single 3 Mg Rasburicase Dose for the Management of Hyperuricemia in Patients with Hematologic Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2479-2479
Author(s):  
Steven M Trifilio ◽  
Judy Pi ◽  
Mary Golf ◽  
Katherine Coyle ◽  
Debbie Greenberg ◽  
...  
Keyword(s):  
Uric Acid ◽  
Serum Creatinine ◽  
Serum Uric Acid ◽  
Baseline Level ◽  
Elevated Serum ◽  
Hematologic Malignancies ◽  
Urate Oxidase ◽  
Fixed Dose ◽  
Absolute Change ◽  
Cent Change

Abstract Abstract 2479 Poster Board II-456 Hyperuricemia(HU) is a frequent complication following therapy for hematologolical malignancies(HM). Conventional therpy with alkalinization, hydration and allopurinol may not be sufficient to lower pre-existingly high uric acid levels(UA). Rasburicase, recombinant urate oxidase, when given at pediatric doses(0.15-.2mg/kg/d x 3-5d)is very effective in lowering UA levels <2mg/dl. The high cost and questionable need to lower UA to near undectectable levels prompted a pre-emptive dose reduced strategy to lower UA. Rasburicase was administered at a single fixed dose of 3 mg to treat 287 episodes of elevated serum UA (>7 mg/dL) in 247 adult patients with hematologic malignancies. 28% had renal failure (serum creatinine >2.5 mg/dL) and 29% had tumor lysis syndrome. The median dose of 36 μg/kg (range 18-65) was a fraction of the recommended pediatric dose of 0.75-1.0 mg/kg over 5 days. The median change in the uric acid levels at 24 hours was -4.1 mg/dL (range -12 to +1) and -45% (range -95 to +9). The uric acid levels normalized at 24 hours in 78% of patients. There was no relationship between the weight-adjusted dose and uric acid decline. The only predictor of resolution of hyperuricemia was baseline uric acid; the failure rate was 84% with baseline uric acid of >12 mg/dL compared to 18% if the baseline level was '12. The level continued to decline beyond 24 hours in the majority of patients in the absence of additional doses. Serum creatinine remained stable over 24 hours and declined over 48 hours and 7 days. There was no relationship between the extent of reduction in uric acid levels and serum creatinine. The approach We conclude that a single 3 mg dose of rasburicase, used with close clinical and laboratory monitoring, is sufficient in most adults with elevated serum uric acid levels up to 12 mg/dL. The best approach to patients with higher levels remains unclear. Table 2: Serum uric acid and creatinine levels and changes (median, range) Serum uric acid (Median, range) Baseline level (mg/dL) 9.3 (7.1–27.3) 24-hour level (mg/dL) 5.3 (0.5–23.0) 24-hour direction of change Any increase 9 (3%) No change 1 (<1%) Any decrease 277 (97%) Increase or <10% decrease 21 (7%) ≥10% decrease 266 (93%) 24-hour absolute change (mg/dL) −4.1 (−12 to +1) 24-hour per cent change (%) −45 (−95 to +9) 24-hour level >7 mg/dL 81 (28%) 24-hour level >5 mg/dL 150 (52%) Serum creatinine (Median, range) Baseline level (mg/dL) 1.7 (0.6–9.7) 24-hour level (mg/dL) 1.6 (0.6–8.7) 24-hour direction of change Any increase 88 (31%) No change 54 (19%) Any decrease 145 (50%) ≥10% increase 52 (18%) <10% change 143 (50%) ≥10% decrease 92 (32%) 24-hour absolute change (mg/dL) −0.1 (−3.3 to +1.4) 24-hour per cent change (%) −3 (−80 to +70) Serum uric acid (mg/dL) 24/7 failure P 24/5 failure P ≤10 13% <0.0001 38% <0.0001 >10 64% 85% ≤12 18% <0.0001 45% <0.0001 >12 84% 93% ≤15 25% <0.0001 50% <0.0001 >15 79% 89% Disclosures: No relevant conflicts of interest to declare.

scholarly journals Control of Plasma Uric Acid in Adults at Risk for Tumor Lysis Syndrome: Efficacy and Safety of Rasburicase Alone and Rasburicase Followed by Allopurinol Compared With Allopurinol Alone—Results of a Multicenter Phase III Study

2010 ◽  
Vol 28 (27) ◽  
pp. 4207-4213 ◽  
Author(s):  
Jorge Cortes ◽  
Joseph O. Moore ◽  
Richard T. Maziarz ◽  
Meir Wetzler ◽  
Michael Craig ◽  
...  
Keyword(s):  
At Risk ◽  
Uric Acid ◽  
High Risk ◽  
Response Rate ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Hematologic Malignancies ◽  
Phase Iii ◽  
Tumor Lysis ◽  
Plasma Uric Acid

Purpose Rasburicase is effective in controlling plasma uric acid in pediatric patients with hematologic malignancies. This study in adults evaluated safety of and compared efficacy of rasburicase alone with rasburicase followed by oral allopurinol and with allopurinol alone in controlling plasma uric acid. Patients and Methods Adults with hematologic malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomly assigned to rasburicase (0.20 mg/kg/d intravenously days 1-5), rasburicase plus allopurinol (rasburicase 0.20 mg/kg/d days 1 to 3 followed by oral allopurinol 300 mg/d days 3 to 5), or allopurinol (300 mg/d orally days 1 to 5). Primary efficacy variable was plasma uric acid response rate defined as percentage of patients achieving or maintaining plasma uric acid ≤ 7.5 mg/dL during days 3 to 7. Results Ninety-two patients received rasburicase, 92 rasburicase plus allopurinol, and 91 allopurinol. Plasma uric acid response rate was 87% with rasburicase, 78% with rasburicase plus allopurinol, and 66% with allopurinol. It was significantly greater for rasburicase than for allopurinol (P = .001) in the overall study population, in patients at high risk for TLS (89% v 68%; P = .012), and in those with baseline hyperuricemia (90% v 53%; P = .015). Time to plasma uric acid control in hyperuricemic patients was 4 hours for rasburicase, 4 hours for rasburicase plus allopurinol, and 27 hours for allopurinol. Conclusion In adults with hyperuricemia or at high risk for TLS, rasburicase provided control of plasma uric acid more rapidly than allopurinol. Rasburicase was well tolerated as a single agent and in sequential combination with allopurinol.

scholarly journals 312 Female sex independently predicts adjuvant immunotherapeutic benefit from CTLA4 immune checkpoint inhibition

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A339-A339
Author(s):  
Ahmad Tarhini ◽  
Ni Kang ◽  
Sandra Lee ◽  
F Stephen Hodi ◽  
Gary Cohen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Efficacy ◽  
Significant Interaction ◽  
Cox Regression ◽  
Performance Status ◽  
Phase Iii ◽  
High Dose ◽  
List Type ◽  
Female Sex ◽  
Interaction Term

BackgroundSex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. Female sex hormones have been implicated in melanoma development and response to systemic therapy. We hypothesized a gender difference in response to adjuvant immunotherapy with ipilimumab (3 or 10 mg/kg; ipi3 or ipi10) versus high dose IFNα (HDI) as tested in the E1609 trial.MethodsE1609 demonstrated significant overall survival (OS) benefit with ipi3 versus HDI.1 We investigated treatment efficacy between ipi and HDI in the subgroups by sex (female, male), age (< 55 or ≥55), stage at study entry (IIIB, IIIC, M1a/1b), ECOG performance status (PS 0, 1), ulceration (yes, no), primary tumor (known, unknown), number of lymph nodes involved (0, 1, 2–3, 4+). Forest plots were created to compare OS and RFS with ipi3 vs. HDI and ipi10 vs. HDI using the concurrently randomized ITT populations. For the estimated HRs, 95% confidence intervals were created for all subgroups.ResultsThe subgroups of female, stage IIIC, PS=1, ulcerated, in-transit without lymph node involvement demonstrated significant improvement in overall survival (OS) and/or relapse free survival (RFS) with ipi3 versus HDI as summarized in table 1. Female sex was significant for both OS and RFS and was further explored. In investigating RFS with ipi3 versus HDI, a multivariate Cox regression model including sex, treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.026). Including sex, PS (0 vs. 1), age (<55 vs. 55+), ulceration (yes vs. no), stage (IIIB, IIIC, M1a, M1b), treatment and interaction term of sex*treatment, indicated a significant interaction between sex and treatment (P = 0.024). While similar trends were seen, no significant interactions between sex and treatment effect were found in the OS multivariate analysis or in the comparison of ipi10 versus HDI. When exploring age, in the univariate analyses in the ipi3 versus HDI comparison older women appeared to drive most of the difference (age ≥55: OS, P=0.02 and RFS, P=0.08; differences non-significant for women <55). Table 1.Abstract 312 Table 1Treatment efficacy between ipi3 and HDI by subgroupConclusionsFemale sex was independently associated with RFS adjuvant immunotherapeutic benefit from ipi3, supporting a potentially important role for female related factors in the immune response against melanoma, and these warrant further investigation.Trial RegistrationNCT01274338Ethics ApprovalThe study protocol was approved by the institutional review board (IRB) of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. This study was monitored by the ECOG-ACRIN DataSafety Monitoring Committee and the NCI.ConsentAll patients provided IRB-approved written informed consent.ReferenceTarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567–575. PMID: 31880964.

Effect and Mechanism of Total Saponin of Dioscorea on Animal Experimental Hyperuricemia

2006 ◽  
Vol 34 (01) ◽  
pp. 77-85 ◽  
Author(s):  
Guang-Liang Chen ◽  
Wei Wei ◽  
Shu-Yun Xu
Keyword(s):  
Uric Acid ◽  
Serum Uric Acid ◽  
Acid Concentration ◽  
Serum Uric Acid Level ◽  
Urate Oxidase ◽  
Uric Acid Concentration ◽  
Total Saponin ◽  
Test Kit ◽  
Serum Uric Acid Concentration ◽  
Potassium Oxonate

In this study, we investigated the effects and mechanisms of Total Saponin of Dioscorea (TSD) on animal experimental hyperuricemia. Mouse and rat hyperuricemic models were made by orally administering yeast extract paste once a day (30 and 20 g/kg, respectively), for 7 days. Yeast would disturb normal purine metabolism by increasing xanthine oxidase (XOD) activity and generating large quantities of uric acid. This model is similar to human hyperuricemia, which is induced by high-protein diets, due to a purine and nucleic acid metabolic disturbance. Another mouse hyperuricemia model was generated by intraperitoneal injection once with uric acid 250 mg/kg or potassium oxonate 300 mg/kg. Potassium oxonate, a urate oxidase inhibitor, can raise the serum uric acid level by inhibiting the decomposition of uric acid. Likewise, injecting uric acid can also increase serum uric acid concentration. The concentration of uric acid in serum or urine was detected by the phosphotungstic acid method, and the activity of XOD was assayed by a test kit. The results showed that TSD (240, 120 and 60 mg/kg, ig) could significantly lower the level of serum uric acid in hyperuricemic mice. TSD (120 and 60 mg/kg, ig) could also lower the level of serum uric acid in hyperuricemic rats, reduce the activity of XOD in the serum and liver of hyperuricemic rats, and increase the level of urine uric acid concentration as well as 24-hour total uric acid excretion. In conclusion, TSD possesses a potent anti-hyperuricemic effect on hyperuricemic animals, and the mechanism may be relevant in accelerating the excretion and decreasing the production of uric acid.

Mechanism of Traditional Medicine Tongfeng Li’an Granules on Hyperuricemic Rats Based on Regulating Uric Acid Transporter

2021 ◽  
Vol 15 (4) ◽  
pp. 536-541
Author(s):  
Xiangpei Zhao ◽  
Li Li ◽  
Chuanmei Zhong ◽  
Hongli Teng ◽  
Guodong Huang
Keyword(s):  
Uric Acid ◽  
Oral Administration ◽  
Natural Product ◽  
Serum Uric Acid ◽  
Rat Model ◽  
Regulatory Mechanism ◽  
High Dose ◽  
Model Group ◽  
Serum Biochemical ◽  
Acid Transporter

Hyperuricemia (HUA) is a metabolic disorder of purine metabolism which leads to the increase of serum uric acid. Tongfeng Lian granule (TFLA) is a clinical empirical traditional herb prescription in China, is biobased natural product material. To study its regulatory mechanism on uric acid transporter in rats with HUA, the rat model of hyperuricemic was established by oral administration of potassium oxazinate (1.5 g/kg) and adenine (0.05 g/kg). The related indexes were detected to evaluate the uric Acid Transporter after treat with TFLA. In the results, compared with model group, the high dose TFLA can reduce the levels of Related serum biochemical indexes (*P < 0.05, **P < 0.01). TFLA could reduce the levels of URAT1, GLUT9 and increase the expression of OAT3 in kidney. In conclusion, TFLA can effectively inhibit the level of serum uric acid with hyperuricemia rats, and the possible mechanism related to TFLA inhibiting the reabsorption of uric acid by URAT1 and GLUT9, promoting the secretion of OAT3 and uric acid into urine.

scholarly journals Risk Factors for Overall Survival in Children with High Risk Acute Myeloid Leukemia (HR AML) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) with Different Intensity of Conditioning Regimens

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Elena Vladimirovna Semenova ◽  
Olesia V Paina ◽  
Zhemal Zarifovna Rakhmanova ◽  
Polina Valerievna Kozhokar ◽  
Anastasia S Frolova ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Performance Status ◽  
Poor Performance ◽  
Poor Performance Status ◽  
Hematopoietic Stem ◽  
Factors Influencing ◽  
Remission Status ◽  
Conditioning Regimens ◽  
The Moment

Background: Traditionally, children with AML undergo аllo-HSCT with myeloablative conditioning (MAC). It is known that MAC is associated with significant transplant-related morbidity and mortality. Reduced-intensity conditioning (RIC) is used in patients not eligible for conventional conditioning therapy due to poor performance status and severe toxic complications after previous chemotherapy. RIC is a well-established treatment strategy in adult patients with comorbidities. But there is no conclusive evidence to support efficacy of RIC allo-HSCT in children suffering from different malignant diseases including AML. The aim: To compare efficacy of different intensity conditioning regimens in children with high risk (HR) AML (according to AML-BFM protocols 1998 and 2004) and to identify factors which have a prognostic significance for overall survival (OS). Patients and methods: Retrospective analysis was performed in 192 patients (pts) with AML (median age of 10 years (0.5-18 y.o.), who received allo-HSCT at R.M. Gorbacheva Research Institute between 08/2000 and 09/2019. MAC (busulfan- or treosulfan-based) were used in 109 pts: 1st CR - 46 pts (MRD+ n=11), 2nd CR - 18 pts, 3rd CR - 1 pt, relapse - 44 pts. Allo-HSCT with RIC were performed in 83 pts: 1st CR - 32 pts (MRD+ n=13), 2nd CR -19 pts, 3rd CR - 4 pts, relapse -28 pts (p=0,674). RIC consisted of fludarabine (30 mg/m2/d x 5 days) + melphalan (70 mg/m2/d x 2 days) or fludarabine (30 mg/m2/d x 5 days) + busulfan (4 mg/kg/d x 2 days). Indication for RIC allo-HSCT was poor performance status (Lansky/Karnofsky score ≤70%), or organ dysfunction due to previous therapy, or infectious complications at the moment of allo-HSCT. Allo-HSCT from matched related donor was performed in 30 pts (16%), from matched unrelated donor - in 98 pts (51%), haploidentical - in 64 pts (33%) and the donor distribution was not different between groups (p=0,878). Post-transplant Cy was included in GVHD prophylaxis regimens in 102 pts (53%). OS were estimated using Kaplan-Meier curves. Univariate analyses were performed using the log rank test for OS, Grey test for cumulative incidences. Multivariate analyses were performed using the Cox proportional-hazard model. Results: Median follow-up was 5 years for МАС, 4.5 years for RIC. In both groups the median time to neutrophil engraftment &gt;=0,5x109/l was D+16 (range D+8-52). Engraftment was observed in 67 pts (81%) after RIC and 94 pts (86%) after MAC (p=0,231). OS after RIC allo-HSCT in the 1st CR was 76% and after MAC - 68% (p=0,014), in 2nd CR 50% after RIC and 54% after MAC (p=0,058), in advanced disease 14% after RIC and 16% after MAC (p=0,394). The transplant-related mortality rate was 19% after RIC and 22% after MAC (p=0,546). Risk of relapse was 28% after RIC and 26% after MAC (p=0,456). Factors influencing OS after MAC were: 1) Remission status at the moment of allo-HSCT (р=0.001); 2) Presence of aGVHD grade I-II (р=0,005); 3) Relapse or MRD+ status after allo-HSCT (р=0.012); 4) Lansky score &gt;70% (р=0,024). Factors influencing OS after RIC were: 1) Remission status at the moment of allo-HSCT (1st remission) (p=0,001); 2) Lansky score &gt;70% (р=0,004). Conclusion: The effectiveness of RIC and MAC is comparable in children with HR AML, but RIC demonstrated better results in 1st CR. The presence of I-II grade aGVHD had positive effect in MAC. Factors influencing OS in both groups were disease status at the moment of allo-HSCT and performance status before allo-HSCT The use of RIC can be effective in patients, especially those who have undergone allo-HSCT in the 1st remission, while minimizing regimen-related toxicity in children who have undergone previous intensive treatment. Multicenter studies are warranted, especially for patients in the first CR, where long-term complications are of most importance. Disclosures No relevant conflicts of interest to declare.

scholarly journals TROG 18.01 phase III randomised clinical trial of the Novel Integration of New prostate radiation schedules with adJuvant Androgen deprivation: NINJA study protocol

BMJ Open ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. e030731 ◽  
Author(s):  
Jarad Martin ◽  
Paul Keall ◽  
Shankar Siva ◽  
Peter Greer ◽  
David Christie ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Controlled Trial ◽  
Performance Status ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
High Dose ◽  
The Novel ◽  
Ecog Performance Status ◽  
Initial Portion ◽  
The Impact

IntroductionStereotactic body radiotherapy (SBRT) is a non-invasive alternative to surgery for the treatment of non-metastatic prostate cancer (PC). The objectives of the Novel Integration ofNew prostate radiation schedules with adJuvant Androgen deprivation (NINJA) clinical trial are to compare two emerging SBRT regimens for efficacy with technical substudies focussing on MRI only planning and the use of knowledge-based planning (KBP) to assess radiotherapy plan quality.Methods and analysisEligible patients must have biopsy-proven unfavourable intermediate or favourable high-risk PC, have an Eastern Collaborative Oncology Group (ECOG) performance status 0-1 and provide written informed consent. All patients will receive 6 months in total of androgen deprivation therapy. Patients will be randomised to one of two SBRT regimens. The first will be 40 Gy in five fractions given on alternating days (SBRT monotherapy). The second will be 20 Gy in two fractions given 1 week apart followed 2 weeks later by 36 Gy in 12 fractions given five times per week (virtual high-dose rate boost (HDRB)). The primary efficacy outcome will be biochemical clinical control at 5 years. Secondary endpoints for the initial portion of NINJA look at the transition of centres towards MRI only planning and the impact of KBP on real-time (RT) plan assessment. The first 150 men will demonstrate accrual feasibility as well as addressing the KBP and MRI planning aims, prior to proceeding with total accrual to 472 patients as a phase III randomised controlled trial.Ethics and disseminationNINJA is a multicentre cooperative clinical trial comparing two SBRT regimens for men with PC. It builds on promising results from several single-armed studies, and explores radiation dose escalation in the Virtual HDRB arm. The initial component includes novel technical elements, and will form an important platform set for a definitive phase III study.Trial registration numberANZCTN 12615000223538.

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