Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes.

Some toxins cause their effects by affecting physiological processes that are fundamental to cell function or cause systemic effects as a result of cellular interaction. This review focuses on four examples, coumarin anticoagulants, isoniazid, methotrexate and thyroxine from the context of management of overdose as seen in acute general hospitals. The current basic clinical pharmacology of the toxin, the clinical features in overdose and evidence base for specific antidotes are discussed. The treatment for this group is based on an understanding of the toxic mechanism, but studies to determine the optimum dose of antidote are still required in all these toxins except thyroxine, where treatment dose is based on symptoms resulting from the overdose.

A case of methotrexate intoxication in a patient with psoriasis who drank beetroot juice during methotrexate treatment.

Methotrexate is extensively used in the treatment of psoriasis. Although safe and effective, its use may inadvertently lead to intoxication. We report a 50-year-old woman being treated with methotrexate for psoriasis who developed methotrexate intoxication after drinking beetroot juice as a herbal remedy. Patients should be warned about the potential adverse effects of herbal therapies during methotrexate treatment.

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.

[Accidental intoxication with methotrexate--a case report]. / Przypadkowe zatrucie metotreksatem--opis przypadku.

The report presents a case of a 49-year-old man, who was accidentally intoxicated with methotrexate. The man was admitted to a nephrology ward because of generalized erythema involving the entire body, skin pruritus, face edema, fever and difficulty with breathing. On the day of admission, additional studies demonstrated a moderate degree of anemia, considerable leucopenia, thrombocytopenia and an increased level of C-reactive protein. In the course of hospitalization, doctors suspected the condition of the patient to be possibly caused by generalized infection, toxic lesion of the bone marrow or hematological bone marrow disease. Finally it was established that the cause of the patient's disease was his erroneous taking of a total of 35 mg of methotrexate (5 mg per day for seven days). Despite intensive treatment, the patient died seven days after admission. Autopsy confirmed that the man died from acute circulatory and respiratory insufficiency caused by intoxication with methotrexate.

[Acute toxicity by methotrexate used for abortion purpose. Case report]. / Intoxicación aguda por metotrexato utilizado con fines abortivos. Reporte de caso.

We report the case of a 16 years old female patient, with a pregnancy history of 11.4 weeks by ultrasound and intrauterine fetal death. In a private clinic were prescribed methotrexate 500 mg intramuscular single dose, and vaginal misoprostol. She had a clinical feature of five days of evolution characterized by fever of 39 degrees C, nausea, general attack and vomiting. The initial diagnosis was severe sepsis secondary to septic abortion, oral candidiasis and acute poisoning by methotrexate. After that, she was referred to the Instituto Nacional de Perinatologia, where stayed with fever for four days, and was managed with hydration, antibiotics, folinic acid and alkalizing. Her recovery was gradual. She was discharged after 12 days with significant clinical improvement. The literature review describes that the use of methotrexate for abortion purpose with therapeutic-dose presents a similar adverse effects to those found in our patient, however there are no case reports that describe the use of this drug in macrodosis for the same purpose, and their cytotoxic effects. We present this case because the patient used a macrodosis of this antimetabolite and due to the premature and empirical management with folinic acid, joined with alkalinization of urine, is the ideal treatment and as it is illustrated in our case.

Use of calcium folinate in the management of accidental methotrexate ingestion in two dogs.

CASE DESCRIPTION: 2 English Pointers were suspected of having consumed toxic doses of methotrexate, a dihydrofolate reductase inhibitor frequently used in human and veterinary chemotherapeutic protocols. CLINICAL FINDINGS: Potentially toxic plasma concentrations of methotrexate were detected in both dogs. Results of physical examination, a CBC, blood gas analysis, and serum biochemical analysis were predominantly unremarkable, although 1 dog had mild hyponatremia (1372 mmol/L; reference range, 140 to 153 mmol/L) and mild hypocalcemia (1.03 mmol of ionized calcium/L; reference range, 1.13 to 1.33 mmol of ionized calcium/L). TREATMENT AND OUTCOME: Point-of-care determination of plasma methotrexate concentrations was not available; thus, palliative care was provided. Emesis was induced in both dogs by SC administration of apomorphine, and 3 doses of a suspension of activated charcoal with sorbitol were administered orally over a 6-hour period. Fluid diuresis was initiated in both dogs by administration of a compound sodium lactate solution, and N-acetylcysteine was administered IV to both dogs as a hepatoprotectant. A solution of calcium folinate (also known as leucovorin) was administered IV to both dogs to mitigate the effects of ingested methotrexate. No adverse effects associated with calcium folinate administration were identified, and no clinical or pathological evidence of methotrexate intoxication was detected. CLINICAL RELEVANCE: IV administration of calcium folinate appeared to prevent the pathological sequelae of methotrexate intoxication without adverse effects. Administration of calcium folinate is recommended for the treatment of dogs with suspected or confirmed methotrexate overdose.

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.

[Severe methotrexate toxicity in elderly: 7 years experience]. / Toxicidad grave por metotrexato en el anciano: nuestra experiencia en los últimos 7 años.

Methotrexate is one of the most widely used drugs in rheumatology due to its high efficacy-to-toxicity. However, patients treated with this drug are sometimes elderly, which increases toxicity risks, as well as mistakes in taking the medication. The case is presented of an 87 year-old patient, on multiple medications, with a history of cognitive impairment and low social support, who suffered acute methotrexate toxicity. A description is also presented on the characteristics of the toxicity cases due this drug admitted to this hospital in the last 7 years.

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.

Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose.

OBJECTIVE: Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose. CASE REPORT: A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17. DISCUSSION: Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate's pharmacokinetics and the patient's normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg.

Methotrexate intoxication: Beyond the adverse events.

AIM: Methotrexate (MTX) is the first-line disease-modifying antirheumatic drug in rheumatoid arthritis (RA). However, this anchor may cause some side effects that may range from nausea to mortality. The clinical features of MTX toxicity are under-researched. In this study, we aimed to find out the potential predisposing factors and outcomes of the MTX toxicity (n = 31). METHODS: The data were collected from 31 patients whose ages ranged from 25 to 81 years, who were suffering from immune-mediated inflammatory diseases and major MTX-related toxicity. RESULTS: Out of 31 patients, six (19.4%) used MTX every day, and 13 (41.9%) patients had renal insufficiency who were admitted to the hospital because of mucositis (90.3%) and fever (71%). While using MTX, 27 patients (87.1%) were discharged after the treatment and four patients (12.9%) died. CONCLUSIONS: Although MTX has high efficacy for the toxicity ratio, wrong use and dosage of MTX may be harmful to patients. Thus, patients should be informed about the proper use of MTX.

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.

Iatrogenically-related, fatal methotrexate intoxication: a series of four cases.

Since the early eighties, the folic antagonist methotrexate (MTX) has been used in long-term treatment of rheumatoid arthritis. Because of the high toxic potential clinical and laboratory controls at regular intervals and patient education in order to avoid misadventure is of overriding importance. We present four cases of fatal MTX intoxication due to medical malpractice from the Tübingen Institute of Forensic Medicine autopsy material, which show the severe consequences of MTX overdose. It becomes evident that among non-rheumatologists there still is need for information about toxicity and dose limitation in MTX low-dose treatment.