Rasburicase for the treatment of tumor lysis in hematological malignancies

Tumor lysis syndrome (TLS) is a common oncologic emergency in patients with hematological malignancies sensitive to cytotoxic treatment that present a high proliferative rate. High proliferative cancer rate, high sensitivity of cytotoxic treatment and renal failure represent risk factors for development of TLS. TLS is also responsible for several electrolytic alterations, such as hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. There are different established therapeutic options for the treatment of TLS such as hydration, allopurinol and rasburicase. Rasburicase reduces uric acid levels within 4 h, both in pediatric and adult patients, catalyzing the oxidation of uric acid into allantoin, rapidly excreted by the kidneys. Rasburicase is well tolerated and was approved in the EU and in the USA for the management of acute hyperuricemia.     

Single dose of rasburicase for treatment of hyperuricemia in acute kidney injury: a report of 3 cases

Severe hyperuricemia accompanied by the other comorbidities such as anuria, fluid overload, calcium-phosphate imbalance, and/or tumor lysis syndrome is one of the indications for dialysis in the setting of acute kidney injury. Rasburicase is used in different clinical conditions such as tumor lysis syndrome and uric acid nephropathy. Among referred patients to our center from 2008 to 2010, there were 3 patients who had an indication for dialysis because of hyperuricemia. Contributing factors to the acute kidney injury were multi-organ dysfunction, rapidly progressive glomerulonephritis, and spontaneous tumor lysis syndrome. None of the patients showed any response to treatment with bicarbonate and hydration. After rasburicase administration, serum uric acid level declined, and urine output increased. Treatment with a single low dose of rasburicase would be effective to decrease the serum uric acid level and reverse kidney injury secondary to uric acid nephropathy.     

Efficacy of rasburicase therapy in obstructive renal failure secondary to urolithiasis: a novel therapeutic option

The overall incidence of nephrolithiasis-related acute and chronic renal failure is poorly known and surely underestimated. However, obstructive nephropathy represents a potentially curable form of kidney disease that often requires for managing an instrumentation of urinary tract. Rasburicase is an enzyme that transforms uric acid to allantoin, a compound more water soluble that will be excreted by the kidney more easily. Rasburicase has been proven to be an effective therapy for prevention of tumour lysis syndrome. But it also represents an interesting new option in managing hyperuricemia in patients with severe tophaceous gout. We administered rasburicase intravenously (0.20 mg/kg/day, for 2 days) in 2 adults with acute obstructive nephropathy from renal calculi, which was receiving temporary haemodialysis. Rasburicase produced a sharp polyuria 12-18 hours after its administration accompanied with a fast reduction of serum creatinine levels, that returned to normal range without further dialysis. If we suppose that rasburicase can pass through glomerular filter by its relatively low molecular weight, it could dissolve tubular uric acid crystals in acute renal failure associated to tumour lysis syndrome, providing the restoration of renal function. But we also could postulate that rasburicase can act in urinary tract, fragmentating renal calculi, promoting relief of obstructive uropathy and the resolution of renal failure. We suggest rasburicase should be tried in this new indication to prove its potential efficacy.     

Recombinant urate oxidase (rasburicase) for the prevention and treatment of tumor lysis syndrome in patients with hematologic malignancies

In this multicenter, nonrandomized, open-label clinical trial conducted from July 2003 to July 2004, recombinant urate oxidase (rasburicase) was administered to patients at risk for tumor lysis syndrome before or during the initiation of chemotherapy. Forty-five patients were enrolled, including 18 children (10 with acute lymphoblastic leukemia, 6 with high-grade lymphoma, and 2 with acute myeloid leukemia) and 27 adults (8 with acute lymphoblastic leukemia, 4 with high-grade lymphoma, 9 with multiple myeloma, and 6 with acute myeloid leukemia). The age ranged from 3 to 98 years, with a median age of 7 years in children and 59.3 years in adults. There were 14 males and 4 females in the pediatric group and 18 males and 9 females in the adult group. Rasburicase 0.2 mg/kg was administered intravenously once a day for 2-6 days, for a median of 3 days in children and of 4 days in adults. After 3 days of treatment, the median uric acid levels in the 18 children decreased from 10.5 mg/dl (range 8-18.6) to 0.5 mg/dl (range 0.0-1.7). Similarly, in the 27 adults, the median levels decreased from 10.8 mg/dl (range 8-24.4) to 0.5 mg/dl (range 0.0-1.6). No significant changes were observed in serum potassium, calcium, and phosphorus concentrations. None of the patients required dialysis for acute renal failure. Rasburicase was very well tolerated, with only 1 adult having grade 1 vomiting. We conclude that rasburicase is safe and highly effective for preventing the complications of tumor lysis syndrome in patients with hematologic malignancies.     

Hyperuricemia and gout

Gout is not a new disease for clinicians; nevertheless, there are still many secrets awaiting discovery for improving knowledge with respect to uric acid metabolism and monosodium urate crystal-induced inflammation. This review of the literature will focus on new insights on the pathogenesis of idiopathic hyperuricemia, and on secondary hyperuricemia and gout. There are also important advances on the pathophysiology of acute gout, especially as a self-limited process (switch from monocyte to macrophage, peroxisome proliferator activated receptor-gamma, and nitric oxide), but also of chronic gouty arthropathy. Armaments for treating hyperuricemia and gout may be already improved by losartan or fenofibrate and, in the future, by urate oxydase-polyethylene glycol 20 and renal handling regulatory molecules. Finally, control of hyperuricemia may also be considered in the prevention and treatment of cardiovascular disease.     

痛风的诊断与治疗

伴随代谢综合征发病率、老年性肾损害患病率的增加及利尿剂的频繁应用，痛风的发病率增加、发病年龄渐年轻化，不典型及难治性痛风增多。痛风的诊断除依据高尿酸血症和临床表现外，还要对其病因、分期及机体损害的部位做出判断，为治疗提供理论依据。痛风的治疗在控制高尿酸血症同时要注意保护脏器、防止急性发作。本文结合新近文献资料，主要介绍了痛风的诊断和治疗，希望对临床医师提供帮助和参考。     

Asymptomatic hyperuricemia: the case for conservative management

The management of asymptomatic hyperuricemia is controversial. Reported benefits from treatment prevention of acute gouty arthritis, chronic tophaceous gout, urolithiasis, or gouty nephropathy. A review of experimental and clinical data suggests that the risks of asymptomatic hyperuricemia are small or unknown and the efficacy of long-term treatment in preventing gout or renal disease is unproved. The costs and risks of prolonged drug administration and practical considerations such as patient compliance mitigate against long-term therapy in asymptomatic persons. We offer some recommendations for an expectant approach to the management of asymptomatic hyperuricemia.     

Acute myocardial infarction associated with acute gouty arthritis

The association of hyperuricemia with increased risk of atherosclerosis has been reported in previous studies but the link of acute gouty arthritis, hyperuricemia and acute myocardial infarction (MI) is not seen frequently. Here we report a 33 year old male who presented with hyperuricemia, acute gouty arthritis and acute myocardial infarction. Hyperuricemia contributed not only to accelerated atherosclerosis but might be blamed for promoting environment for acute myocardial infarction.     

Failure of rasburicase therapy in recurrent acute gout with tophi

Rasburicase, a recombinant urate oxidase enzyme, has been used successfully in several cases of chronic tophaceous gout. We report the case of an elderly woman with chronic tophaceous gout who failed rasburicase therapy due to recurrent acute episodes of gout following each rasburicase infusion, despite prophylactic therapy.     

A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis

Standard therapy in the United States for malignancy-associated hyperuricemia consists of hydration, alkalinization, and allopurinol. Urate oxidase catalyzes the enzymatic oxidation of uric acid to a 5 times increased urine soluble product, allantoin. Rasburicase is a new recombinant form of urate oxidase available for clinical evaluation. This multicenter randomized trial compared allopurinol to rasburicase in pediatric patients with leukemia or lymphoma at high risk for tumor lysis. Patients received the assigned uric acid-lowering agent for 5 to 7 days during induction chemotherapy. The primary efficacy end point was to compare the area under the serial plasma uric acid concentration curves during the first 96 hours of therapy (AUC(0-96)). Fifty-two patients were randomized at 6 sites. In an intent-to-treat analysis, the mean uric acid AUC(0-96) was 128 +/- 70 mg/dL.hour for the rasburicase group and 329 +/- 129 mg/dL.hour for the allopurinol group (P <.0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% CI: 2.0-3.4) less exposure to uric acid. Four hours after the first dose, patients randomized to rasburicase compared to allopurinol achieved an 86% versus 12% reduction (P <.0001) of initial plasma uric acid levels. No antirasburicase antibodies were detected at day 14. This randomized study demonstrated more rapid control and lower levels of plasma uric acid in patients at high risk for tumor lysis who received rasburicase compared to allopurinol. For pediatric patients with advanced stage lymphoma or high tumor burden leukemia, rasburicase is a safe and effective alternative to allopurinol during initial chemotherapy.     

Uric acid levels and platelet function in humans. An in-vivo ex-vivo study

Platelet function (aggregation by ADP, adrenaline, collagen and circulating platelet aggregates) before, during and after dietary induction of hyperuricemia (ribonucleic acid, 3 g/day) was studied in five healthy volunteers to assess the relationship between uric acid level and platelet function. In the same subjects, during a second period of ribonucleic acid diet, the acute and chronic effects of a hypo-uricemizing agent, allopurinol, were assessed. No significant correlation was detected between platelet function and uricemia either in the absence or in the presence of pharmacological treatment with allopurinol. On the basis of these results, the well known relationship between uric acid levels and ischemic heart disease does not appear to be mediated by an exaggerated platelet function.     

Hyperuricemia and gout: diagnosis and therapy

In our modern society hyperuricemia is one of the most frequent metabolism disturbances. So far, every fourth man and every tenth woman suffer from an asymptomatic or a symptomatic hyperuricemia named gout. Mostly, over nutrition and malnutrition as well as other secondary factors with a genetically determined renal secretion disturbance of uric acid lead to an increase of serum uric acid. By deposition of uric acid crystals in tissues with intermittent immunologic activation of inflammation cells a manifestation of gout can be seen. The clinical image of gout varies widely. It may manifest as acute or chronic arthritis, tophi on the skin, subcutaneous tissue and the skeletal system as well as urate nephropathy. To eliminate the consequences of hyperuricemia in the long term, apart from a thorough anamnesis of nutritional habits a general examination of metabolic parameters is necessary to exclude a metabolic syndrome and other causes for a secondarily caused hyperuricemia. As gout is very often primarily caused by a renal secretion disturbance of uric acid special diagnostics should be done. Basing on literature research and inclusion of experts opinions this article represents the therapeutically options in treatment of hyperuricemia and gout with their resulting side effects and contraindications.     

Gout and hyperuricemia

Gout continues to be a health problem around the world despite the availability of effective therapies. Although the prevalence is influenced by genetic factors, the associations of alcohol consumption, obesity, and hypertension appear to be partially responsible for the increased prevalence of gout and hyperuricemia in African and Oriental countries. The association between hyperuricemia and cardiovascular disease seems linked to insulin resistance. This relation, in part, explains the common coexistence of hyperlipidemia and glucose intolerance in patients with gout. Accordingly, it is recommended that one pay more attention to dietary manipulation in patients with gout in addition to managing hypertension, obesity, and other medical problems. Although acute gout attacks can be treated, eliminating gout requires effective removal of urate from the body. Allopurinol remains a dominant urate-lowering agent, however its use may be limited by allergic reactions. Uricosuric agents are also effective urate-lowering agents and provide an alternative to allopurinol. Strategies to treat patients who are sensitive to allopurinol continue to evolve.     

Emerging therapies in the long-term management of hyperuricaemia and gout

Gout is a common chronic arthritis that can lead to significant disability. Gout is one of the few rheumatological conditions that can be diagnosed with certainty, has a known cause and can be cured with appropriate therapy. Hypouricaemic agents reduce uric acid concentrations through inhibiting uric acid production (allopurinol) or enhancing uric acid excretion (probenecid, benzbromarone). Allopurinol is the most commonly used hypouricaemic agent but at recommended doses often fails to reduce adequately uric acid concentrations and prevent acute attacks of gout. The use of probenecid is limited by lack of efficacy in renal impairment. In the last few years, new agents in the management of hyperuricaemia and gout have become available. Febuxostat, a new xanthine oxidase inhibitor, is an effective hypouricaemic agent although further data are required for patients with renal impairment and other significant medical conditions. Rasburicase, a recombinant uricase (which catalyses the conversion of uric acid to the more readily excreted allantoin) is available for prevention of tumour lysis syndrome. However, its repeated use, as would be required in chronic gout, is limited by antigenicity. A less antigenic PEGylated uricase can rapidly reduce serum uric acid concentrations and promote resorption of tophi. However, further information with regard to the long-term risks and benefits of these agents is required. These agents may ultimately be used in the short term to rapidly deplete urate stores (induction therapy) followed by long-term therapy with an alternative hypouricaemic agent to prevent subsequent accumulation of uric acid (maintenance therapy).     

Hépatite aigu? cytolytique induite par l’allopurinol chez un patient traité pour hépatite virale C

Allopurinol is a drug indicated for the treatment of hyperuricemia. Its hepatic toxicity is rare. This is a case report about acute cytolytic hepatitis caused by allopurinol in a 65-year-old patient undergoing dual therapy for hepatitis C.     

Management of gout and hyperuricemia: Multidisciplinary consensus in Taiwan

Gout is an inflammatory disease manifested by the deposition of monosodium urate (MSU) crystals in joints, cartilage, synovial bursa, tendons or soft tissues. Gout is not a new disease, which was first documented nearly 5,000 years ago. The prevalence of gout has increased globally in recent years, imposing great disease burden worldwide. Moreover, gout or hyperuricemia is clearly associated with a variety of comorbidities, including cardiovascular diseases, chronic kidney disease, urolithiasis, metabolic syndrome, diabetes mellitus, thyroid dysfunction, and psoriasis. To prevent acute arthritis attacks and complications, earlier use of pharmacotherapeutic treatment should be considered, and patients with hyperuricemia and previous episodes of acute gouty arthritis should receive long‐term urate‐lowering treatment. Urate‐lowering drugs should be used during the inter‐critical and chronic stages to prevent recurrent gout attacks, which may elicit gradual resolution of tophi. The goal of urate‐lowering therapy should aim to maintain serum uric acid (sUA) level <6.0 mg/dL. For patients with tophi, the initial goal can be set at lowering sUA to <5.0 mg/dL to promote tophi dissolution. The goal of this consensus paper was to improve gout and hyperuricemia management at a more comprehensive level. The content of this consensus paper was developed based on local epidemiology and current clinical practice, as well as consensuses from two multidisciplinary meetings and recommendations from Taiwan Guideline for the Management of Gout and Hyperuricemia.     

急性肿瘤溶解综合征的临床特点、治疗与预后(附20例报告)

目的 探讨急性肿瘤溶解综合征(ATLS)的临床特点、治疗及预后。方法 对20例ATLS患者的临床资料进行回顾性分析。结果 肿瘤恶性程度高、临床分期晚、肿瘤体积大、恶性淋巴瘤、白血病为ATLS的高危因素，患者均表现不同程度的高钾血症、高磷血症、高尿酸血症、低血钙及肾功能不全。5本病，及时诊断并纠例死亡患者中，4例死于ATLS。结论 ATLS见于各种肿瘤化疗后，临床医生应熟悉正电解质紊乱、改善肾功能是改善患者预后的关键。     

《2010年中国痛风临床诊治指南》解读

《2010年中国痛风临床诊治指南》指出,在诊断痛风时要特别注意痛风患者的病程阶段:即无症状高尿酸血症、急性痛风性关节炎或慢性痛风,强调关注患者是否为无症状高尿酸血症或痛风合并其它情况(糖尿病、高血压病,或心脑血管的危险因素)。除了合理应用非甾类抗炎药或糖皮质激素积极治疗急性关节炎急性发作外,痛风患者的综合管理尤为重要,包括对所有患者去除引起高尿酸血症的诱因及给予非药物干预(生活方式和饮食调整、减轻体重、适度饮酒,停用引起尿酸升高的药物等),有效控制合并症。对反复发作的、间歇期或慢性痛风患者给予降尿酸药物治疗以维持血尿酸水平低于327μmol/L,以及为严重的慢性痛风石患者寻找可能的手术治疗机会。     

高尿酸血症大鼠血尿酸与血管内皮功能相关性的研究

目的：探讨高尿酸大鼠血尿酸与血管内皮功能的关系。方法：雄性SD大鼠36只,随机均分为正常对照组、模型组和别嘌醇治疗组。使用高酵母膏饲料联合氧嗪酸钾腹腔注射6周诱导大鼠高尿酸模型。别嘌醇治疗组除给予造模剂外同时以别嘌醇灌胃6周。定期测量大鼠收缩压。6周后处死大鼠,检测各组血清尿酸（SUA）、一氧化氮（NO）、内皮素-1（ET-1）、收缩压（SBP）等的变化,用免疫组化法检测大鼠主动脉内膜层内皮型一氧化氮合酶（eNOS）的表达量。结果：与正常对照组相比,模型组大鼠SUA水平[（45.1±5.6）μmol/L∶（216.0±6.2）μmol/L]显著升高（P〈0.001）,ET-1[（85.4±8.7）μg/L∶（163.1±7.2）μg/L]、SBP[（115.7±4.1）mm-Hg∶（156.0±3.8）mmHg]显著升高,血NO[（24.1±2.0）μmol/L∶（17.2±3.4）μmol/L]及主动脉内膜层eNOS[（48.3±4.2）∶（38.3±4.5）]表达量显著降低（P均〈0.05）;与模型组比较,别嘌醇组SUA[（44.8±4.3）μmol/L]、ET-1[（92.8±5.0）μg/L]、SBP[（119.2±4.3）mmHg]水平显著降低,血NO[（22.1±2.2）μmol/L]和主动脉内膜eNOS的表达量（46.1±4.2）明显升高（P均〈0.05）,别嘌醇组与正常对照组比较上述指标无明显差异（P〉0.05）。SUA与SBP、ET-1呈正相关（r=0.98、0.98,P均〈0.001）,与NO呈负相关（-0.70,P〈0.001）。结论：高尿酸血症与大鼠血管内皮功能紊乱密切相关。血一氧化氮的降低和内皮素-1的升高可能是发生高血压的重要原因之一。别嘌醇具有保护血管内皮功能的作用。     

A study of rasburicase for the management of hyperuricemia in pediatric patients with newly diagnosed hematologic malignancies at high risk for tumor lysis syndrome

Tumor lysis syndrome (TLS), including hyperuricemia, is a frequent serious complication in patients with hematologic malignancies. This study in Japanese patients evaluated the efficacy, safety, and pharmacokinetic profile of rasburicase in pediatric patients with hematologic malignancies. Patients aged <18 years at high risk for TLS, with newly diagnosed hematologic malignancies, were randomized to intravenous rasburicase 0.15 mg/kg/day (n = 15) or 0.20 mg/kg/day (n = 15) for 5 days. Chemotherapy was started 4–24 h after the first rasburicase dose. Response was defined as a reduction in plasma uric acid to ≤6.5 mg/dL (patients <13 years) or ≤7.5 mg/dL (patients ≥13 years) by 48 h after the first administration, lasting until 24 h after the final administration. Response rates were 93.3 and 100% with rasburicase 0.15 and 0.20 mg/kg/day, respectively. Uric acid levels declined rapidly within 4 h of starting rasburicase administration in both groups. Most adverse events were related to the underlying chemotherapy regimens. Two hypersensitivity reactions, including grade 1/2 pruritus, were considered to be related to rasburicase. Rasburicase is effective and well tolerated for the management of hyperuricemia in Japanese pediatric patients at high risk of developing TLS.