Resumption of high-dose methotrexate after methotrexate-induced nephrotoxicity and carboxypeptidase G2 use.

PURPOSE: The successful resumption of high-dose methotrexate in a 13-year-old boy with recurrent anaplastic large-cell lymphoma (ALCL) who suffered renal dysfunction after a 24-hour infusion of high-dose methotrexate and required treatment with carboxypeptidase G(2) (CPDG(2) ) is described. SUMMARY: A 13-year-old boy who had been diagnosed in 2001 with stage I ALCL was admitted to the hospital in February 2005 after he developed a smaller left axillary mass in the area of his original mass. Recurrent ALCL was diagnosed, and treatments were initiated based on branch K3 of the protocol published in the non-Hodgkin's lymphoma-Berlin-Frankfurt-Münster (NHL-BFM) trial 90. In the NHL-BFM 90 protocol, all AA and BB courses include high-dose methotrexate therapy, which consists of aggressive alkalinized hydration, methotrexate 5 g/m(2) given as an i.v. infusion over 24 hours, and leucovorin rescue. During course BB2, the boy's serum methotrexate values exceeded NHL-BFM goals at 36, 42, and 48 hours. Because the patient's elimination of methotrexate remained slow and his serum creatinine level remained above normal limits, CPDG(2) was obtained for the treatment of methotrexate toxicity. The patient tolerated the CPDG(2) without adverse effects, and the patient's serum methotrexate concentration decreased from 14.47 to 0.66 microM. The patient went on to complete six courses based on the protocol. High-dose methotrexate was resumed at 50% then 100% of the original dose. He is currently in remission on maintenance therapy. CONCLUSION: A 13-year-old boy with recurrent ALCL had methotrexate-induced nephrotoxicity following high-dose methotrexate. The resultant delayed methotrexate clearance required the standard therapies as well as use of investigational CPDG(2). High-dose methotrexate was successfully resumed.     

Managing reduced methotrexate clearance in a patient with a heterozygous methylenetetrahydrofolate reductase gene polymorphism

High dose methotrexate has become one of the treatments of choice for patients with primary CNS lymphomas due to its ability to penetrate the blood-brain barrier. A potentially serious complication of this therapy is methotrexate-related nephrotoxicity. We report the case of a patient with a common genetic polymorphism that may have predisposed this patient experience clinically significant toxicity from systemic folate depletion. After the first cycle of chemotherapy that included high dose methotrexate, the patient's serum creatinine rose and the patient's methotrexate level remained above the toxic range for six days. On cycle two, the patient was treated with a 25% dose reduction in methotrexate and more aggressive hydration and alkalization. With this alteration in the regimen, the patient was able to receive six more cycles and had a complete radiographic tumor response in the brain and a disappearance of tumor cells in the CSF without any further renal complications. This case report illustrates the feasibility of administering high dose methotrexate with modifications as a treatment of choice in individuals with methylenetetrahydrofolate reductase gene mutations.     

大剂量甲氨蝶呤化疗致急性肾衰竭2例

2例患者大剂量甲氨蝶呤（MTX）化疗导致急性肾衰竭。第l例为53岁女性，因非霍奇金淋巴瘤给予大剂量MTX化疗：先用MTX500mg0．5h时内静脉滴注、3500mg24h内泵入，然后用亚叶酸钙进行解救，首次剂量为30mg／m^2，以后15mg／m^2，每隔6h肌内注射1次，解救8次。患者无慢性肾脏病史，化疗前肾功能正常（SCr97．1μmot／L，BUN4．78mmol／L）。化疗后第4天，出现颜面及双手轻度水肿，尿量减少，SCr升至151Ixmol／L。给予甲泼尼龙、呋塞米和碳酸钙一维生素D3对症治疗，并碱化尿液，监测肾功能（SCr最高达275μmot／L），化疗后第13天肾功能恢复至正常（SCr96μmol／L）。第2例为29岁男性，因急性淋巴细胞白血病给予大剂量MTX化疗：MTX500mg0．5h内静脉滴注、4500mg24h内泵入，解救方案同例1。患者无慢性肾脏病史，化疗前肾功能正常（SCr86．9μmol／L，BUN5．35mmol／L）。化疗后第3天出现全身水肿、尿量减少，SCr升至235μmol／L（最高达360μmol／L）。给予对症治疗，同例1。化疗后第30天肾功能恢复至正常（SCr89ttmol／L）.     

Pharmacokinetic interaction between high-dose methotrexate and oxacillin

An 18-year-old man received two high-dose methotrexate cycles for the treatment of an osteosarcoma. Fifteen grams of methotrexate were infused over 6 hours. During the second cycle, co-administration of oxacillin (1g/8h) resulted in prolonged and marked elevation of methotrexate plasma concentrations. The patient experienced acute toxicity with renal failure, myelosuppression, mucitis, fever, and dermatologic abnormalities. After an initial improvement with folinic acid rescue and hemodialysis, the patient died. Oxacillin may thus inhibit the elimination of methotrexate.     

Unrecognized acute lithium toxicity: a case report

We report a case of a 63-year-old male who has been admitted to the Emergency department with nonspecific symptoms. Lithium toxicity was not at first recognized. When we obtained sufficient information about previous medication and medical history, we measured lithium levels found to be 1.46 mmol/L. Although the value of lithium was mildly elevated, nephrotoxicity was produced leading to severe renal insufficiency and neurological symptoms. Hemodialysis was started, and we succeed to treat the patient without squeals. This case illustrates some of the factors that lead to lithium toxicity as well as the need to consider lithium toxicity to the differential diagnosis of a patient presenting with renal insufficiency with or without change in mental status and neurologic symptom.     

Increased methotrexate toxicity due to concurrent probenecid administration

The toxicity of a single dose of methotrexate in the rat was observed to be substantially increased when probenecid was concurrently administered. The increased toxicity was associated with a marked inhibition of the elimination of methotrexate from the blood. The effects of probenecid on the renal and biliary secretion of methotrexate were determined using steady state conditions. Inhibition of biliary secretion accounted for most of the decreased elimination of methotrexate.     

Clinical use of thymidine as a rescue agent from methotrexate toxicity

Summary Thymidine has been available for clinical research as a rescue agent since 1978 under sponsorship of the Division of Cancer Treatment, National Cancer Institute. Renal insufficiency following administration of high dose methotrexate results in prolonged exposure to toxic concentrations of drug. Thymidine has been used in conjunction with leucovorin and alkaline hydration to protect patients with acute renal dysfunction from life-threatening methotrexate toxicity. The outcome of eight cases in which thymidine was released under the special exception mechanism to treat patients who developed acute renal failure following methotrexate are reported. The clinical trials using thymidine in combination with methotrexate in patients with normal renal function are also reviewed.     

Cola beverage and delayed elimination of methotrexate

AIMS

To report a case of severe delayed methotrexate elimination attributable to consumption of a cola beverage.

METHODS

To investigate unexplained low urinary pH in a lymphoma patient treated with high-dose methotrexate.

RESULTS

Unexpected urinary acidity, despite administration of large amounts of sodium bicarbonate, could be attributed to repeated consumption of a cola beverage. It resulted in a delayed elimination of methotrexate and acute renal failure. Discontinuation of cola drinks, increase in calcium folinate rescue and in sodium bicarbonate allowed satisfactory elimination of methotrexate on day 12 after infusion and recovery from renal impairment without other severe toxicity. No other cause of delay in methotrexate elimination could be identified.

CONCLUSIONS

Cola beverages have a low pH due to their phosphoric acid content that is excreted by renal route. We recommend patients receiving high dose methotrexate abstain from any cola drink within 24 h before and during methotrexate administration and until complete elimination of the drug.     

Interaction between methotrexate and omeprazole in an adolescent with leukemia: a case report

We present a case of severe mucositis due to a drug-drug interaction between methotrexate (MTX) and omeprazole in an adolescent with Acute Lymphatic Leukemia (ALL). In view of the prevalence of MTX in many cytotoxic protocols, and the frequent use of omeprazole in the (ambulatory) oncology setting, we believe that this case-report is worth mentioning.     

High-dose methotrexate with folinic acid rescue.

A brief review of the pharmacology of methotrexate is presented, and the rationale for the administration of high-dose methotrexate and the necessity of a folinic acid rescue to prevent methotrexate toxicity are discussed. Critical factors concenrning the use of this therapy, as well as unusual toxicities associated with the use of high-dose methotrexate, are presented. Several drug-and patient-related variables which may affect the toxicity of this dual drug administration are discussed to better enable pharmacists to monitor patients receiving this form of therapy. High-dose methotrexate with folinic acid rescue has improved the therapeutic index of methotrexate. The optimal dosage and duration of the two agents are yet to be determined.     

Plasma digoxin concentration fluctuations associated with timing of plasma sampling and amiodarone administration

A 31-year-old man with dilated cardiomyopathy was hospitalized for new-onset atrial fibrillation. Oral amiodarone 600 mg/day was started to control his arrhythmia, and the patient continued to receive digoxin 0.125 mg/day, which was prescribed 4 days earlier at a heart failure clinic. The patient's digoxin plasma concentration peaked early on hospital day 3 at 2.93 ng/ml; digoxin was withheld. Over the next 3 days, the patient's digoxin plasma concentrations rose and fell daily. These fluctuations correlated with the timing of blood sampling in relation to oral amiodarone administration. The patient's renal function remained stable, and he developed no signs or symptoms of digoxin toxicity. To our knowledge, no case reports have associated significant fluctuations of digoxin plasma concentrations that correspond to the timing of oral amiodarone administration. Tissue-to-plasma redistribution appears to be a possible mechanism for this interaction, with the most significant effect occurring 8-10 hours after amiodarone administration. Clinicians should be aware that digoxin plasma concentrations may not correlate with digoxin tissue concentrations in this setting. When a loading dose of oral amiodarone is required in a patient receiving digoxin, the digoxin dosage should first be reduced, and digoxin therapy should be adjusted based on signs and symptoms of digoxin toxicity.     

A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination

Human multidrug resistance protein 2 (MRP2, encoded by ABCC2) is involved in active efflux of anionic drugs such as methotrexate. MRP2 is expressed on the luminal side of hepatocytes and renal proximal tubular cells, indicating an important role in drug elimination. We postulated that loss-of-function mutations in ABCC2, which are involved in the Dubin-Johnson syndrome, may be associated with impaired methotrexate elimination and an increased risk of toxicity. We studied the biological phenotype and ABCC2 coding sequence in a patient receiving a high-dose methotrexate infusion for large B-cell lymphoma and who had an unusual pharmacokinetic profile, mainly characterized by a three-fold reduction in the methotrexate elimination rate. This resulted in severe methotrexate over-dosing and reversible nephrotoxicity. An inversion of the urinary coproporphyrin isomer I/III ratio (a specific biological marker of the Dubin-Johnson syndrome) was observed in this patient. Genetic analysis of ABCC2 identified a heterozygous mutation replacing a highly conserved arginine by glycine in the cytoplasmic part of the second membrane-spanning domain (position 412 of MRP2), a region associated with substrate affinity. This genetic variant was not found in a control population. Functional analysis in transiently transfected Chinese hamster ovary cells revealed a loss of transport activity of the G412 MRP2 mutant protein. An ABCC2 mutation altering MRP2-mediated methotrexate transport and resulting in impaired drug elimination and subsequent renal toxicity was identified. Candidates for methotrexate therapy should be considered for MRP2 functional testing.     

Acute cardiac toxicity associated with high-dose intravenous methotrexate therapy: case report and review of the literature

A 36-year-old woman was hospitalized for preoperative chemotherapy for osteosarcoma. She received intravenous fluids for 12 hours for volume expansion, then methotrexate 24 g (12 g/m2) over 6 hours. This was followed by intravenous leucovorin 200 mg over 1 hour. Two hours after the methotrexate infusion the patient developed chest pain and bradycardia. An electrocardiogram revealed sinus pauses, and telemetry recordings indicated a 4-beat run of ventricular tachycardia. A cardiac work-up consisting of cardiac enzyme level determination, two-dimensional echocardiography, and an adenosine technetium-99m tetrofosmin stress test was negative for structural and ischemic heart disease. The patient recovered without treatment and, approximately 2 weeks later, received a second course of methotrexate at half the dose without complication. One month later the patient received treatment with doxorubicin and cisplatin; 2 days later she died unexpectedly at home. Clinicians should be aware that high-dose methotrexate can cause cardiac symptoms and arrhythmias in previously healthy adults. This complication warrants attention and needs additional clinical investigation.     

Fatal acute encephalomyelitis after a single dose of intrathecal methotrexate

A 40-year-old Hispanic man with acute lymphoblastic leukemia was treated with a single dose of intrathecal methotrexate 12 mg for prophylaxis against leptomeningeal spread of tumor. The day after methotrexate administration, the patient complained of severe back pain and urinary retention. The diagnosis of encephalomyelitis was made on day 3 after methotrexate administration, and by day 6 mechanical ventilation was begun secondary to ascending paralysis. By day 8 the patient was comatose, with minimal signs of brain activity and little hope for recovery; on day 12 he died. Although neurotoxicity is a frequent complication of methotrexate therapy, fatal acute neurotoxicity is extremely uncommon, especially in adults. The mechanisms of methotrexate toxicity remain unclear, and no effective treatment exists to prevent its occurrence. This patient rapidly progressed from mild neurotoxicity to fatal encephalopathy after one dose of intrathecal methotrexate during his third cycle of chemotherapy. Clinicians should be aware of the signs and symptoms of neurotoxicity during treatment, as well as predisposing factors that put patients receiving methotrexate at risk for neurotoxic effects.     

Pancytopenia after a single intradermal infiltration of methotrexate

Methotrexate-related hematologic toxicity may include leukopenia, thrombocytopenia, megaloblastic anemia, and pancytopenia. We report a woman with hypertensive renal disease who was receiving hemodialysis and developed pancytopenia following a single intradermal infiltration of 25 mg of methotrexate. Caution should be exercised when considering the use of either systemic or intralesional methotrexate therapy in patients with risk factors that have been implicated in the development of adverse hematologic side effects: renal dysfunction, possible drug interactions, and advanced age.     

Statin toxicity: a situation that mimics viral hepatitis

A case is presented involving a female patient who experienced rhabdomyolysis following high-dose therapy with a statin. Acute renal failure was a complicating factor necessitating the use of hemodialysis. The patient recovered fully within about 6 weeks.     

Treatment of hyperkalemia in a patient with unrecognized digitalis toxicity

Cardiac glycoside toxicity is frequently associated with hyperkalemia and dysrhythmias in patients with renal insufficiency. Two common therapeutic options for these complications (calcium and transvenous cardiac pacing) are considered contraindicated in the setting of cardiac glycoside toxicity. We present the case of a patient presenting with a pronounced bradydysrhythmia and hyperkalemia who was treated with intravenous calcium and transvenous cardiac pacing and later found to have digitalis toxicity and acute renal failure. There were no adverse events associated with the therapies. The patient received digoxin-specific Fab fragments and hemodialysis as definitive therapeutic modalities. The case and the relevant literature evaluating the interaction of calcium salts and cardiac pacing in the setting of cardiac glycoside toxicity are discussed.     

Reversibility of the toxicity of methotrexate by dihydrofolate in mice

1. Dihydrofolate in mice can reverse the toxicity of a lethal dose of methotrexate. 2. The 'rescue' of mice after a lethal dose of methotrexate suggests that dihydrofolate could have a clinical use as an antidote in treating methotrexate-induced toxicity.     

A fatal outcome in a patient with glioblastoma multiforme after receiving high-dose methotrexate.

The most common adult primary brain tumor is glioblastoma multiforme (GBM). Current treatment is surgical resection, adjuvant radiation and chemotherapy, which can extend the median survival 20-36 weeks (Mansky et al. Central nervous system tumors. In Abraham J, Allegra CJ, Gulley J, eds. Bethesda Handbook of clinical oncology, 2nd edn. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins, 2000: 440-2; Knox S. Intracranial tumors. In Pillot G, Chantler M, Magiera H, Peles S, et al., eds. The Washington Manual Hematology and Oncology Subspecialty Consult. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins, 2004: 204-6.). But treatment efficacy is limited, mandating the exploration of more effective treatments. We report on a patient with GBM treated as per a clinical protocol with high-dose methotrexate (12 g/m(2)), who expired within hours after the initiation of treatment secondary to transtentorial herniation. Although it is not completely clear what caused the patient's herniation, we think that high-dose methotrexate therapy may have played a crucial role. We suggest that high-dose methotrexate should be used cautiously in patients with GBM.     

Compatibility and toxicity of methotrexate in the treatment of bone tumors

Chemotherapeutical treatment with high dose methotrexate (HD-MTX) of osteogenic sarcoma has been performed at the Orthopaedic University Clinic of Vienna since 1975. In accordance with the cooperative study for osteosarcoma (Coss) which has been in use in Germany and Austria since 1977, HD-MTX has been used in larger quantity beside other cytostatic drugs. The total of 4259 g MTX has been applied to 36 patients who were suffering from malignant bone tumors. We report about the toxicity and compatibility of MTX. Within 231 cycles of treatment in 8 cases a high toxicity (grade IV after modified WHO-Score) was found. One patient died in consequence of the chemotherapy by fungal infection.