Real-time comprehensive toxicology testing in the clinical management of accidental pediatric capecitabine ingestion.

INTRODUCTION: Capecitabine is an orally bioavailable prodrug of the chemotherapeutic agent, fluorouracil. Fluorouracil is converted to several active metabolites that induce a cytotoxic effect. Capecitabine toxicity can be life-threatening with a delayed presentation from ingestion. An oral antidote, uridine triacetate, exists but requires the administration of 20 total doses over a course of five days. CASE REPORT: In this report, we describe a case where timely coordination with a clinical toxicology laboratory was utilized to drive clinical decision making and management. Two children were brought to the emergency department shortly after suspected capecitabine ingestion. MANAGEMENT AND OUTCOME: Patients were admitted to the hospital and started on uridine triacetate. Real-time comprehensive toxicology testing of the children's blood was used to rule out capecitabine toxicity and prevent several unnecessary days of hospitalization and doses of antidote. Patients were discharged safely. DISCUSSION: Real-time comprehensive toxicology testing on a patient's blood may be a valuable resource in ruling out or confirming toxic exposure in accidental pediatric ingestion of chemotherapeutic agents like capecitabine when performed in a timely manner.

Acute versus chronic methotrexate poisoning; a cross-sectional study.

BACKGROUND: Data is limited on comparison of acute and chronic methotrexate (MTX) poisoning. Methotrexate is an anti-folate drug that may be prescribed in some malignant or chronic inflammatory conditions. The aim of the current study was to compare signs and symptoms, complications, treatment and final outcome of acute and chronic MTX toxicity. METHOD: In a retrospective study in a referral center between March 2010 and March 2018, all patients who had been referred with the history of MTX poisoning and hospitalized due to acute or chronic poisoning were evaluated and compared. RESULTS: Of the total 27 patients admitted during the study period, 13 had referred with acute (group 1; consumption of MTX for less than 7 days) and 14 had referred with chronic toxicity (group 2; consumption of MTX for more than 7 days). Mean age was significantly higher in the second group (P < 0.001). Median total dose of MTX was similar between the groups (P = 0.90). Mucosal ulcers and skin lesions (P < 0.001 and 0.02, respectively) were the only symptoms significantly different between the two groups. Leukopenia (P < 0.001), thrombocytopenia (P < 0.001), and anemia (P = 0.04) were significantly more common in the second group. Blood urea nitrogen and creatinine were also significantly higher in the second group of the patients (P < 0.001 and P = 0.048). Median leucovorin administered dose was 200 mg [14, 480] versus 150 mg [75, 187] (P = 0.69) in groups 1 and 2, respectively. CONCLUSIONS: Chronic MTX poisoning is more serious than acute toxicity and accompanies higher dermatologic, hematologic, and hepatic complications necessitating more aggressive treatments including administration of higher doses of leucovorin or bone marrow stimulants such as G-CSF. This may be attributable to the underlying diseases and features (including older ages) which predispose these patients to complications.

Evaluation of toxicity after acute accidental methotrexate ingestions in children under 6 years old: a 16-year multi-center review.

CONTEXT: There is little data on the frequency of adverse events following acute methotrexate ingestions in pediatric patients. Likewise, recommendations for observation length, site and management strategies in this population are not well established. Therefore, most recommendations are modeled after management of chronic overdose in patients with underlying medical conditions. OBJECTIVE: The primary objective of this study is to determine the frequency of acute toxicity after acute methotrexate accidental unsupervised ingestions in patients less than six years. In addition, we describe the frequency of late toxicity and characterize the management site and approaches. MATERIALS AND METHODS: This is a retrospective cohort study of pediatric accidental unsupervised methotrexate ingestions reported to six poison centers in the United States over a 16 year period. Demographic information, exposure details, signs, symptoms, treatments, length and location of observation and outcomes were collected. RESULTS: 103 patients met inclusion criteria. Methotrexate dose was reported in 86 patients (84%) and ranged from 1.3 mg-75 mg. The majority of cases (97%) ingested a dose ≤20 mg. The significant majority of cases experienced no clinical effects (99 of 103 cases; 96%). Three children experienced minor outcome (3%). There were no patients with a major outcome or death. CONCLUSIONS: The incidence of toxicity from pediatric single, acute ingestions of methotrexate is rare and when it occurs is generally limited to no or only minimally concerning effects. Because concentrations from single ingestions were consistent with low subtoxic exposures, we believe that home monitoring without hospital referral and without methotrexate specific therapy is reasonable in those with acute ingestions up to 20 mg.

What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning?

CONTEXT: Methotrexate (MTX) is an anti-folate drug that has been utilized in both malignant and chronic inflammatory conditions. Doctors are often concerned with a potential adverse outcome when managing patients with acute oral MTX poisoning given its potential for serious adverse reactions at therapeutic doses. However, there is surprisingly little data from acute poisoning cases and more data from the therapeutic use of high-dose MTX. OBJECTIVES: To review pharmacokinetic and pharmacological properties of MTX and systematically review series of acute MTX poisonings and therapeutic studies on high-dose MTX that provide pharmacokinetic or clinical data. METHODS: An Embase (1974-October 2016) and Medline (1946-October 2016) search was performed by combining "MTX" and "overdose/poison" or "MTX" and "toxicity" or "MTX" and "high-dose MTX" or "MTX" and "bioavailability" or "pharmacokinetics"; 25, 135, 109 and 365 articles were found, respectively, after duplicates were removed. There were 15 papers that provided clinical data on acute ingestion and toxicity that occurred with low-dose administration. Eighteen papers were on high-dose MTX (>1 g per m2 body surface area) used as a single chemotherapy agent which provided pharmacokinetic or clinical data on MTX toxicity. Thirty papers were reviewed to determine the toxic dose, pharmacokinetics, risk factors, clinical symptoms and management of acute MTX toxicity. Given the limited acute poisoning data, a retrospective audit was performed through the consultant records of the New South Wales Poisons Information Centre from April 2004 to July 2015 to examine the clinical syndrome and toxicity of acute oral MTX poisoning. Pharmacokinetics: Reduced MTX bioavailability is a result of saturable absorption. Although maximal bioavailable absorption occurs at a dose of ∼15 mg m-2, splitting the dose increases bioavailability. MTX clearance is proportional to renal function. Acute toxicity: Oncologists prescribe doses up to 12 g m-2 of MTX. Patients treated with an intravenous dose of MTX <1g m-2 do not require folinic acid rescue. MTX toxicity correlates better with duration and extent of exposure than peak serum concentration. Acute oral poisoning: Acute oral MTX poisoning in 177 patients did not report any severe toxicity. In the New South Wales Poisons Information Centre audit data (2004-2015), 51 cases of acute MTX poisoning were reported, of which 15 were accidental paediatric ingestions. The median reported paediatric ingestion was 50 mg (IQR: 10-100; range: 10-150) with a median age of 2 years (IQR: 2-2; range: 1-4). Of the 36 patients with acute deliberate MTX poisoning, median age and dose were 47 years (IQR: 31-62; range: 10-85) and 325 mg (IQR: 85-500; range: 40-1000), respectively. Of the 19 patients who had serum MTX concentrations measured, all were significantly below the concentrations used in oncology and the folinic acid rescue nomogram line and no patient reported adverse sequelae. Management of acute oral poisoning: Due to the low bioavailability of MTX, treatment is not necessary for single ingestions. Oral folinic acid may be used to lower the bioavailability further with large ingestions >1 g m-2. Oral followed by intravenous folinic acid may be used in patients with staggered ingestion >36 h or patients with acute overdose and renal impairment (eGFR <45 mL/min/1.73 m2). CONCLUSIONS: As a consequence of saturable absorption MTXs bioavailability is so low that neither accidental paediatric MTX ingestion nor acute deliberate MTX overdose causes toxicity. An acute oral overdose will not provide a bioavailable dose even close to 1 g m-2 of parenteral MTX. Hence, no treatment is required in acute ingestion unless the patient has renal failure or staggered ingestion. There is also no need to monitor MTX concentrations in acute oral MTX poisoning.

The successful treatment of 5-fluorouracil (5-FU) overdose in a patient with malignancy and HIV/AIDS with uridine triacetate.

According to the NIH, about 275000 patients receive treatment with 5-Fluorouracil (5-FU) and more than 1300 die from 5-FU toxicity every year from life-threatening myelosuppression, gastrointestinal complications, and neurotoxicity. Immunocompromised persons are at higher risk of developing toxicity. Recently uridine triacetate (Vistagard®) has been approved by the Food and Drug Administration (FDA) as the only specific antidote available for 5-FU poisoning. In a clinical trial (n=135), 96% of patients with 5-FU toxicity recovered after treatment, where as in a historical control group only 10% survived. This is the first published case report of survival after 5-FU overdose who also was immunocompromised from HIV/AIDs. A 52year old male with history of HIV/AIDS (CD4 70), CNS toxoplasmosis and anal cancer presented to the emergency department after realizing he had received an entire course of 5-FU in 24 instead of 96h. Treatment with uridine triacetate was arranged in the emergency department. After receiving treatment the patient was asymptomatic and had an uncomplicated hospital course. 5-FU poisoning must be recognized early as uridine triacetate is approved by the FDA for use within 96h following the end of 5-FU administration. Emergency medicine physicians should promptly recognize and treat 5-FU poisoning. However, this may be challenging as patients may not seek medical attention until many hours or several days after last administration since symptoms are often delayed with 5-FU poisoning.

A Large Case Series of Acute Pediatric Methotrexate Ingestions: Significant Clinical Effects Are Rare.

OBJECTIVE: Significant adverse effects after acute pediatric methotrexate (MTX) exposures have been limited to parenteral exposures. Treatment recommendations for pediatric MTX exposures do not differentiate between routes of exposure. We report the incidence of significant clinical effects and drug-specific treatments reported in a large series of acute, pediatric MTX ingestions. METHODS: Poison center records of all MTX ingestions by patients younger than 17 years during 2000 to 2005 were collected from 6 poison centers. The cases included all MTX ingestions including those with additional substances. One trained reviewer, blinded to the study purpose, used a standardized data collection form to extract study data. Missing or conflicting data were reconciled with predetermined process. RESULTS: Forty-seven cases were documented for 6 years, 42 (89%) of which were unintentional. Thirty-six percent (17/47) were male. The mean age for the unintentional ingestions was 3.7 years (range, 20 days-17 y; median, 2 y). Five cases (11%) were intentional suicidal ingestions in teenagers. The mean dose in acute, unintentional ingestions (AUIs) in all children and in children younger than 6 years was the same, 8 mg (range, 2.5-17.5 mg). Eleven patients (23%) had follow-up greater than 12 hours. No patient with an AUI developed MTX-induced sedation, hepatotoxicity, renal insufficiency, seizures, or bone marrow suppression. Three patients with an AUI received folinic acid, but no patients in this group received sodium bicarbonate or hemodialysis. One patient with an intentional suicidal exposure developed hepatotoxicity, but the patient also ingested a toxic dose of acetaminophen and valproate. Hemodialysis was performed once on this patient. No patient died. CONCLUSIONS: Acute pediatric MTX ingestion is uncommon. Methotrexate-induced seizure, renal failure, hepatic injury, and sedation were not documented in our series. Supportive care and observation only should be considered the mainstay of treatment of pediatric AUIs. Prospective verification of our findings is warranted.

[YAKTON INFLUENCE ON THE RABBITS CARDIAC ACTIVITY AND SYSTEMI HEMODYNAMIC IN THE CONDITIONS OF 5-FLUOROURACILUM INTOXICATION].

In the experiments on the rabbits the disturbances of cardio and systemic hemodynamic after 5-fluorouracilum administration have been shown. Yakton administercd intravenously in dose 560 mg/ kg one hour before 5-fluorouracilum protects the disturbances of cardio- and systemic hemodynamic data in animals.

The utility of online haemodiafiltration in methotrexate poisoning.

Summary We report a case of a 56-year-old woman with a high-grade diffuse large B-cell lymphoma who unexpectedly developed toxic plasma levels of methotrexate (MTX) following the first cycle of rituximab-cyclophosphamide, hydroxydanorubicin, oncovin, prednisolone (R-CHOP) with a high-dose MTX chemotherapy protocol. She also developed non-oliguric acute kidney injury secondary to MTX nephrotoxicity. We elected to treat her with online-haemodiafiltration (HDF) and this proved to be efficient with a dramatic response. Rapid clearance of MTX to therapeutic levels was possible within three sessions. Prompt therapy with high-volume online-HDF is an effective choice for rapid MTX clearance and swift reversal of MTX nephrotoxicity.

Fatal methotrexate toxicity: could it have been avoided?

Methotrexate is used judiciously, only when specifically indicated. However, in this case the patient had a fatal outcome after only three doses. A young nulliparous woman diagnosed as having high-risk persistent trophoblastic disease was considered for multidrug chemotherapy. However, because of persistent low-grade fever it was decided to give only single agent, methotrexate. She developed severe toxicity which proved fatal, even before the first course could be completed. Analysing causes of this rare, unexpected outcome of methotrexate administration, suggested that estimation of serum levels can be a useful tool in monitoring patients showing hypersensitivity but this facility is rarely available especially in low-resource countries. Pharmacogenetical analysis of blood/tissue sample may be useful to help in identifying patients likely to show hypersensitivity reaction.

Use of uridine triacetate for the management of fluorouracil overdose.

PURPOSE: The use of uridine triacetate for the management of fluorouracil toxicity is reported. SUMMARY: A 55-year-old man with malignant neoplasm of the sigmoid colon (stage IIIC) was seen in an outpatient chemotherapy center for his first six-month regimen of leucovorin calcium, fluorouracil, and oxaliplatin. Fluorouracil 2400 mg/m(2) i.v. was prescribed to be given over the next 46 hours at a home infusion center. Due to a medication error, a home infusion pharmacist incorrectly programmed the 46-hour infusion of fluorouracil to be administered over 4 hours. To manage the fluorouracil overdose, the physician decided to start the patient on uridine triacetate. The patient received his first dose of uridine triacetate 18 hours after the fluorouracil overdose. He was admitted to the hospital for observation and daily laboratory tests during treatment with uridine triacetate. He received ondansetron (as the hydrochloride salt) 8 mg orally 20 minutes before each dose of uridine triacetate to prevent nausea and vomiting. Uridine triacetate 11 g every 6 hours was administered orally for a total of 20 doses. It was mixed with applesauce at the time of administration and followed with 8 oz of water. The patient's laboratory values remained stable. The patient did not experience any nausea or vomiting during treatment. He was discharged from the hospital on day 5, with no clinical complications and an Eastern Cooperative Oncology Group Performance score of 0. CONCLUSION: A patient with colon cancer who had received an overdose of fluorouracil was successfully treated with a five-day course of oral uridine triacetate.

Severe intoxication with methotrexate possibly associated with concomitant use of proton pump inhibitors.

BACKGROUND: Delayed elimination of methotrexate associated with serious side-effects has been attributed to the co-administration of benzimidazole proton pump inhibitors. PATIENTS AND METHODS: We have retrospectively analyzed the causes of delayed methotrexate elimination in patients who had received the rescue agent glucarpidase to evaluate the potential implication of benzimidazoles. RESULTS: Between 2002 and 2008, six patients (mean age: 30 years; range: 4-74 years) were treated with glucarpidase. Delayed elimination associated with impaired renal function occured after the first cycle except in 2 patients (2nd and 8th administration of high-dose methotrexate). The possible causes of delayed elimination identified were: insufficient hydration (n=1) and drug-drug interactions (n=5). The potential drug-drug interactions included the co-administration of piperacillin/tazobactam (n=1) and proton pump inhibitors (omeprazole, n=3; esomeprazole, n=2). Impaired elimination of methotrexate was not observed either in the 3 patients who were treated further or during the previous cycles of the 2 pretreated patients in relation to the absence of co-prescription of proton pump inhibitors. CONCLUSION: In line with the recent literature and given the prohibitive cost of glucarpidase, we have advocated the cessation of proton pump inhibitors administration during methotrexate treatment.

Treatment of methotrexate intoxication with various modalities of continuous extracorporeal therapy and glucarpidase.

Methotrexate, administered for treatment of pediatric and adult malignancies, is a direct renal toxin, which can lead to renal dysfunction, decreased methotrexate clearance, elevated methotrexate concentrations, and systemic toxicity. Although plasma methotrexate concentrations have been shown to decline precipitously after a single dose of glucarpidase, this drug is investigational and available only through compassionate use. Therefore, alternative treatments for methotrexate removal may be required. We describe a 13-year-old girl (body surface area 1.2 m(2)) with osteosarcoma who was treated with high-dose methotrexate 12 g/m(2) infused over 4 hours. Forty-eight hours after the infusion, her plasma methotrexate concentrations were elevated at 446 micromol/L. She exhibited severe signs of methotrexate toxicity, including encephalopathy, liver failure, and acute kidney injury, and could not tolerate conventional hemodialysis. Over the next 12 days, the patient was treated with continuous venovenous hemodialysis (CVVHD), single-pass albumin dialysis (SPAD), continuous venovenous hemodiafiltration (CVVHDF), and glucarpidase to enhance methotrexate elimination. Compared with standard CVVHD, SPAD did not significantly increase methotrexate removal as measured by elimination half-life and methotrexate saturation coefficient. The highest clearance rate among extracorporeal therapies was achieved by CVVHDF, with an effluent rate of 4950 ml/hour. The patient's clinical condition steadily improved, and all extracorporeal therapies were stopped 168 hours after methotrexate administration. The patient was discharged home and continued with chemotherapy, including methotrexate, which was dosed based on iothalamate glomerular filtration rates on the day before infusion. Although extracorporeal treatments appeared to enhance methotrexate clearance, the administration of glucarpidase resulted in the most rapid percentage decline (86%) in methotrexate concentration. Until glucarpidase is readily available, intermittent hemodialysis should be used to enhance methotrexate clearance. If the patient is unable to tolerate hemodialysis, use of CVVHDF with maximum effluent rates will enhance methotrexate clearance.

The presentation of 6-mercaptopurine overdose in ED.

6-Mercaptopurine (6-MP), although an effective immunosuppressive when used in the treatment of certain cancers, can have devastating effects when ingested accidentally or used in excessive amounts. We report here the case of an unintentional ingestion of a large amount of 6-MP by a woman with hypothyroidism who was erroneously given this antimetabolic agent by her pharmacist instead the propylthiouracil (PTU) she was actually prescribed. This is one of several documented cases in which 6-MP has been dispensed instead of PTU. Because of the myelosuppressive and hepatotoxic effects of 6-MP, this case reinforces the need for both physicians and patients to understand the importance of examining their medications before ingestion.

Delayed recognition of intrathecal methotrexate overdose.

A 10-year-old girl who presented to our hospital was diagnosed as having B-precursor cell acute lymphoblastic leukemia. St Jude's Total XIII protocol was started. In the second block of the consolidation phase, 10 hours after triple intrathecal treatment, we realized that instead of 12 mg, 120 mg of methotrexate had accidentally been given. Although the patient had no symptoms 10 hours after intrathecal treatment, to prevent the possible neurotoxic effects of methotrexate, a cerebrospinal fluid exchange was performed. Simultaneously, systemic dexamethasone and calcium folinic acid were given. At the time of this writing (2 y), the patient has had no symptoms and has continued on the chemotherapy protocol as planned. Administration of high-dose intrathecal methotrexate may not lead to symptoms, as was the case in our patient. This may be related to individual variations in cerebrospinal fluid dynamics and drug metabolism.

Four-year experience with methotrexate exposures.

INTRODUCTION: Unintentional methotrexate (MTX) acute oral overdose is rarely reported. METHODS: We conducted a retrospective chart review of all human exposure calls (>150,000 charts) for MTX ingestions reported to our Poison Center during 2000-2003. RESULTS: Thirteen patients met the criteria. The average amount of MTX ingested was 13.03 mg (data from 7 cases), and the average patient age was 43 years (20 months to 80 years). No significant toxicities occurred. DISCUSSION: Although intravenous MTX toxicity can be severe, this does not appear to be a phenomenon associated with either acute unintentional or suicidal oral ingestion.

Acute methotrexate neurotoxicity: findings on diffusion-weighted imaging and correlation with clinical outcome.

BACKGROUND AND PURPOSE: Acute lymphocytic leukemia (ALL) is a common malignancy of childhood treated with methotrexate (MTX), which is associated with acute neurotoxicity. We evaluated diffusion-weighted (DW) and conventional MR images in children with ALL and acute MTX-induced neurotoxicity, with clinical correlation. METHODS: Five patients aged 12-15 years underwent fluid-attenuated inversion recovery (FLAIR), T2-weighted fast spin-echo and gradient-echo, T1-weighted gadolinium-enhanced spin-echo, and DW imaging within 24 hours of symptom onset. Records were reviewed for the temporal relationship to MTX administration, strokelike symptoms, and neurologic outcome. RESULTS: Six strokelike events were temporally related to intrathecal MTX given 6-11 days before symptom onset. FLAIR images showed abnormal hyperintensity in the callosal splenium in one patient but were otherwise normal. Diffusion abnormalities were frontoparietal in three events and frontal in one; nonfluent aphasia was seen in all. Bilateral frontoparietal diffusion abnormalities were associated with bilateral upper-extremity weakness, right-sided hemiparesis, or left-sided hemiparesis (one patient each); one patient had mild facial droop. Unilateral precentral subcortical diffusion abnormality was associated with contralateral motor deficit and ipsilateral upper-extremity sensory loss. Strokelike symptoms resolved rapidly and were not associated with other signs of encephalopathy. Subsequent intrathecal MTX administration was not associated with recurrence in four patients. CONCLUSION: Diffusion abnormalities in acute MTX neurotoxicity indicated cerebral dysfunction but not necessarily overt structural injury to the cerebrum. Subsequent demyelination or gliosis could not be predicted on the basis of diffusion abnormalities. A single strokelike episode with diffusion abnormalities should not necessarily prompt modification of potentially curative chemotherapeutic regimens.