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AMINOPTERIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aminopterin is a folic acid antagonist that is structurally similar to methotrexate. It is 10 times more potent than methotrexate.

Specific Substances

    1) Aminopteridine
    2) A-ninopterin
    3) APGA
    4) ENT 26,079
    5) NSC 739
    6) 4-Aminopteroylglutamic acid
    7) 4-Aminopteroylglutamate
    8) N-(4-(2,4-Diaminopteridin-6-ylmethyl)amino)benzoyl-L(+)-glytamic acid
    9) Molecular Formula: C19-H20-N8-O5
    10) CAS 54-62-6
    1.2.1) MOLECULAR FORMULA
    1) C19-H20-N8-O5

Available Forms Sources

    A) USES
    1) RODENTICIDE - U.S. patent to American Cyanamid (Windholz, 1983)
    2) Aminopterin was being investigated as a potential form of treatment for acute leukemia in children (Sollman, 1957). In 1985, aminopterin was removed from the National Cancer Institute's list of investigational drugs.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Aminopterin is a folic acid antagonist, structurally similar to methotrexate. Bone marrow hypoplasia, nausea, vomiting, anorexia and fetal death or abnormalities may occur with aminopterin overdose.
    B) Aminopterin is structurally related to methotrexate and might produce similar toxic effects.
    0.2.8) GASTROINTESTINAL
    A) Diarrhea, stomatitis, anorexia, and GI hemorrhage were noted as toxic effects.
    0.2.13) HEMATOLOGIC
    A) Leukopenia, granulocytopenia, lymphopenia, thrombocytopenia and hypoplasia of all elements of bone marrow may occur with aminopterin overdose.
    0.2.14) DERMATOLOGIC
    A) Alopecia has been described.
    0.2.20) REPRODUCTIVE
    A) Numerous anomalies have been reported in children who were exposed to aminopterin in utero. No data were available to assess the potential effects of exposure to this agent during lactation.
    0.2.21) CARCINOGENICITY
    A) Carcinogenesis studies are inconclusive.

Laboratory Monitoring

    A) Monitor CBC with differential and platelet count, liver and renal function.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) LEUCOVORIN - Reduces the risk of hematopoietic toxicity by supplying the necessary tetrahydrofolate cofactor, the synthesis of which is blocked by aminopterin.
    D) Folic acid is NOT an effective antidote.
    E) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists.

Range Of Toxicity

    A) Minimum lethal human exposure is unknown.
    B) Small doses of aminopterin may result in some aplasia of bone marrow.

Clinical Effects

Summary Of Exposure

    A) Aminopterin is a folic acid antagonist, structurally similar to methotrexate. Bone marrow hypoplasia, nausea, vomiting, anorexia and fetal death or abnormalities may occur with aminopterin overdose.
    B) Aminopterin is structurally related to methotrexate and might produce similar toxic effects.

Heent

    3.4.4) EARS
    A) DEAFNESS - Was noted as a toxic symptom during clinical trials (Stickney et al, 1948).

Gastrointestinal

    3.8.1) SUMMARY
    A) Diarrhea, stomatitis, anorexia, and GI hemorrhage were noted as toxic effects.
    3.8.2) CLINICAL EFFECTS
    A) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) Stomatitis was noted as a toxic effect during clinical trials (Farber et al, 1948; Stickney et al, 1948). Stomatitis may occur with aminopterin overdose (HSDB , 2002).
    B) DIARRHEA
    1) Diarrhea occurred as a toxic symptom during clinical trials (Stickney et al, 1948).
    C) LOSS OF APPETITE
    1) Anorexia may occur with aminopterin overdose (HSDB , 2002).
    D) GASTROINTESTINAL HEMORRHAGE
    1) Gastrointestinal bleeding has occurred from treatment of acute leukemia in children (Sollman, 1957).
    E) NAUSEA AND VOMITING
    1) Nausea and vomiting may occur with aminopterin overdose (HSDB , 2002).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANOREXIA
    a) Anorexia was noted in studies with rats (Higgins, 1949).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) In a study to determine maximum tolerated dose of aminopterin, 3 of 20 patients developed hepatic toxicity. It was limited to aminotransferase level elevation with no clinical evidence of hepatic dysfunction (Ratliff et al, 1998).

Hematologic

    3.13.1) SUMMARY
    A) Leukopenia, granulocytopenia, lymphopenia, thrombocytopenia and hypoplasia of all elements of bone marrow may occur with aminopterin overdose.
    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) HEMATOPOIESIS - Suppression of bone marrow has been noted in clinical studies (Phillips & Thiersch, 1949). In one study of 9 patients, the onset of decreased total cell count of the marrow was within 10 days from the onset of treatment (Thiersch, 1949). It may occur more quickly after an overdose.
    2) When aminopterin is withdrawn, the bone marrow usually will spontaneously return to normal in about 18 days, or earlier if folic acid is given (Thiersch, 1949).
    3) Hypoplasia of all elements of bone marrow, with leukopenia, granulocytopenia, lymphopenia, and thrombocytopenia, may occur with aminopterin overdose (HSDB , 2002).

Dermatologic

    3.14.1) SUMMARY
    A) Alopecia has been described.
    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) Alopecia was noted as a toxic effect during clinical trials (Stickney et al, 1948; Karnofsky et al, 1950).

Reproductive

    3.20.1) SUMMARY
    A) Numerous anomalies have been reported in children who were exposed to aminopterin in utero. No data were available to assess the potential effects of exposure to this agent during lactation.
    3.20.2) TERATOGENICITY
    A) HUMANS
    1) In the offspring of women, aminopterin caused specific developmental abnormalities of the eye and ear, craniofacial area (including nose and tongue), musculoskeletal system and central nervous system. Other types of developmental abnormalities were also detected (HSDB , 2002; Shaw & Rees, 1980; Warkany et al, 1959; Meltzer, 1956; Emerson, 1962; Brandner & Nussle, 1969; Gellis & Feingold, 1979).
    2) Club foot has been reported in infants born to mothers who ingested aminopterin during pregnancy (Cowell & Wein, 1980).
    3) Aminopterin Syndrome (AS) is a name describing a recognizable pattern of human malformation. The phenotype of the children who survived infancy despite early prenatal exposure to aminopterin includes: a very unusual facies, skull anomalies and skeletal defects (Krajewska-Walasek, 1994).
    4) The most frequently observed effects noted have been abnormalities in skull development, facial defects, micrognathia, and often palatal defects, as well as maldevelopment of long bones, with defects of linear growth, bony development, and club foot (Shaw & Rees, 1980; Warkany et al, 1959; Meltzer, 1956; Emerson, 1962; Brandner & Nussle, 1969; Gellis & Feingold, 1979; Cowell & Wein, 1980).
    5) Bony defects of the skull, arms, and legs, and growth retardation in a single fetus were associated with maternal ingestion of aminopterin from day 55 to 58 of pregnancy (Shaw, 1972). Follow-up at 17.5 years of age indicated that the skeleton appeared normal. Only micrognathia remained (Shaw & Rees, 1980).
    6) These effects were observed in offspring of women receiving therapeutic doses of aminopterin in clinical trials for the treatment of leukemia; a threshold dose below which these effects would NOT be produced has not been defined.
    7) Aminopterin Syndrome Sine Aminopterin (ASSA) Syndrome refers to children who have the phenotype of AS but have no history of prenatal exposure to aminopterin (Krajewska-Walasek, 1994).
    8) An additional toxic effect observed in newborns exposed in utero to aminopterin was a change in apgar score (RTECS , 2002).
    B) ANIMAL STUDIES
    1) RAT - In rat studies, aminopterin was observed to cause fetotoxicity, fetal death, homeostasis, and developmental abnormalities of the musculoskeletal system, central nervous system, craniofacial area (including nose and tongue), body wall and other areas. In mouse studies, fetotoxicity and changes in the live birth index and viability index were observed (HSDB , 2002; RTECS , 2002).
    2) RABBIT - Aminopterin induced multiple birth defects and/or lethality in the offspring of rabbits at a dose of 15 mg/kg on day 12 of gestation (Goeringer & DeSesso, 1990). Leukovorin, a structural analog of folinic acid, partially prevented the adverse reproductive effects of aminopterin in rabbits (Goeringer & DeSesso, 1990). Extraembryonic structures were observed in aminopterin-exposed rabbits (RTECS , 2002).
    3) DOG - Specific developmental abnormalities of the body wall and musculoskeletal system, as well as changes in newborn growth statistics were observed in dog studies (RTECS , 2002).
    4) PIG - Specific abnormalities in the craniofacial area (including the nose and tongue) and musculoskeletal system were also observed in pig studies (RTECS , 2002).
    3.20.3) EFFECTS IN PREGNANCY
    A) HUMANS
    1) ABORTION
    a) Abortions were observed in women who ingested aminopterin.
    2) SKELETAL MALFORMATION
    a) Bony defects of the skull, arms, and legs in a fetus were associated with maternal ingestion of aminopterin from day 55 to 58 of pregnancy (Shaw, 1972).
    1) On follow-up at 17.5 years of age, the skeletal defects appeared normal. Only micrognathia remained (Shaw & Rees, 1980).
    3) GROWTH RETARDED
    a) Growth retardation in a fetus was associated with maternal ingestion of aminopterin from day 55 to 58 of pregnancy (Shaw, 1972).
    4) PREGNANCY CATEGORY
    AMINOPTERINX
    Reference: Briggs et al, 1998

    B) ANIMAL STUDIES
    1) RAT - In rat studies, aminopterin caused post-implantation mortality (RTECS , 1991).
    2) MOUSE - In mouse studies it caused a change in the female fertility index (RTECS , 2002).
    3) DOG - Abortion as well as post-implantation mortality were observed in dog studies (RTECS , 2002).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation.

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS54-62-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Carcinogenesis studies are inconclusive.
    3.21.3) HUMAN STUDIES
    A) LEUKEMIA
    1) Aminopterin was found to be an equivocal tumorigenic agent by RTECS criteria with leukemia induction (RTECS , 2002).

Genotoxicity

    A) Chromosome aberrations have been noted with therapeutic use.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor CBC with differential and platelet count, liver and renal function.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Because aminopterin may potentially produce abnormalities of the hematopoietic system, liver, and kidneys, monitoring complete blood count (with differential and platelet count), urinalysis, and liver and kidney functions tests is suggested for patients with significant exposure.
    2) Abnormalities may take days to develop. Therefore, serial measurements over time may be necessary to detect abnormalities.
    4.1.3) URINE
    A) URINARY LEVELS
    1) Folic acid antagonists decrease urinary 17-ketosteroids in acute leukemia patients. This can be overcome by administration of corticotropin (Sollman, 1957).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor for signs and symptoms of infection or bleeding during neutropenic and thrombocytopenic phase.

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) A linear relationship exists between the concentration of aminopterin in an aqueous solution and the fluorescence of its oxidized product. Aminopterin can be detected by fluorescence of its oxidized metabolite; activation is at approximately 360 micrometers, and fluorescence is at approximately 460 micrometers (Freeman & Zubrod, 1956).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Carefully observe patients with ingestion exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.
    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) Patients symptomatic following exposure should be observed in a controlled setting until all signs and symptoms have fully resolved.
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    6.3.5) DISPOSITION/DERMAL EXPOSURE
    6.3.5.5) OBSERVATION CRITERIA/DERMAL
    A) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

Monitoring

    A) Monitor CBC with differential and platelet count, liver and renal function.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) LEUCOVORIN
    1) Leucovorin (Citrovorum Factor, Folinic Acid): Eliminates the hematopoietic toxicity by supplying the necessary tetrahydrofolate cofactor, the synthesis of which is blocked by aminopterin.
    2) DOSE -
    a) Dosage of leucovorin in humans to reverse toxicity from an overdose is unknown. In one experimental animal study, approximately 150 micrograms of leucovorin had to be administered to prevent toxicity of 10 micrograms of aminopterin (De Renzo & Dessau, 1954).
    b) Dosage of leucovorin used for methotrexate toxicity is highly controversial. It is generally recommended that doses of leucovorin equal to, or greater than, the ingested dose of methotrexate be given. Lower doses are used during routine therapy with methotrexate in an attempt to protect normal body cells but not tumor cells.
    c) Leucovorin has few side effects and is a relatively safe antidote.
    3) EFFICACY - Leucovorin is most effective for methotrexate toxicity if given within 4 hours postexposure.
    4) FOLIC ACID: Folic acid is NOT an effective antidote because folic acid requires reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates. Folinic acid (leucovorin) is the active (reduced) form of folic acid (Kastrup, 1989) and requires no conversion for efficacy.
    B) ALKALINIZATION REGIME
    1) Administration of sodium bicarbonate for alkalinization of the urine to a pH of 7 or greater will prevent precipitation of methotrexate in the kidney and may enhance elimination. Urinary alkalinization should be considered in severe overdoses.
    2) There are no studies showing that this procedure is effective for aminopterin, but aminopterin is more soluble in alkaline conditions (Reynolds, 1988), so theoretically this procedure might help with elimination.
    3) DOSE - 3000 milliliters/square meter/day of dextrose 5% in water with 40 milliequivalents/liter of sodium bicarbonate. Administer potassium with careful monitoring of renal status.
    4) The theoretically desirable urine flow is pH dependent (Sasaki et al, 1984):
    URINE pHURINE FLOW
    70.1 to 1.8 mL/min/m(2)
    65 to 11.1 mL/min/m(2)
    51.9 to 42.2 mL/min/m(2)

    C) THYMIDINE
    1) Rescues cells from cytotoxic effects of methotrexate by thymidylate salvage; theoretically, it might work for aminopterin.
    2) DOSE: No data are available for aminopterin. Eight grams/square meter/day by continuous intravenous infusion until methotrexate serum level is less than 5 x 10(-7) Molar has been suggested for treatment of methotrexate toxicity.
    3) AVAILABILITY: National Cancer Institute Investigational Drug Branch as 15 grams in 500 milliliters of 0.6 percent (V/V) sodium chloride (Abelson et al, 1983).
    D) VITAMIN A
    1) In a study to determine the maximum tolerated therapeutic dose of aminopterin, the dose limiting toxicity was mucosal ulceration. Vitamin A was used with success in healing mucosal ulceration in these patients. Daily dose was 5000 IU (Ratliff et al, 1998).
    E) MONITORING OF PATIENT
    1) Obtain a baseline CBC and monitor renal and hepatic function closely.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) Minimum lethal human exposure is unknown.
    B) Small doses of aminopterin may result in some aplasia of bone marrow.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Aminopterin is not effective for acute leukemia in adults (Sollman, 1957).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) INFANTS - 0.25 milligram 3 to 6 times weekly for 3 or more weeks until the blood and the bone marrow function are restored to normal or until toxic effects appear (Sollman, 1957).
    2) CHILDREN - 0.5 milligram 3 to 6 times weekly for 3 or more weeks until the blood and the bone marrow are restored to normal or until toxic effects appear (Sollman, 1957).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    2) Small doses may result in some aplasia of bone marrow (Sollman, 1957).
    3) In one study, the maximum tolerated dose was 2 milligram/meter squared every 12 hours for two doses weekly with a leucovorin rescue of 5 milligrams/meter squared orally every 12 hours for two doses, starting 24 hours after the second dose of aminopterin (Ratliff et al, 1998).
    4) The dose limiting symptom is mucosal toxicity (Ratliff et al, 1998).

Workplace Standards

    A) ACGIH TLV Values for CAS54-62-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS54-62-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS54-62-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS54-62-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 2002
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1900 mcg/kg
    2) LD50- (ORAL)MOUSE:
    a) 3 mg/kg
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 3 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) In animal studies, aminopterin interfered with the conversion of folic acid to citrovorum factor. It blocks both the formation of citrovorum factor and its utilization (Sollman, 1957).

Toxicologic Mechanism

    A) Aminopterin induced toxicity is only partially reversed by folic acid and citrovorum factor (Sollman, 1957).
    B) In animal studies, aminopterin interfered with the conversion of folic acid to citrovorum factor; it depresses hematopoiesis and may be toxic to all reticulo-endothelial tissue (Sollman, 1957).
    C) In patients with pernicious anemia, aminopterin blocks the hematological response to folic acid, liver extract, and vitamin B12 (Sollman, 1957).

Physicochemical

Physical Characteristics

    A) Aminopterin occurs as orange-yellow powder or as clusters of yellow, needle-shaped crystals (Reynolds, 1988; (EPA, 1985).

Ph

    A) 6.5-8.5 (INVESTIGATIONAL DRUG PRODUCT, reconstituted solution)

Molecular Weight

    A) 440.47 (EPA, 1985) Reynolds, 1988)

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) CHICK EMBRYO - A marked inhibition of growth of the chick embryo occurs following exposure to 4-amino derivatives of folic acid (Karnofsky et al, 1949).
    11.1.3) CANINE/DOG
    A) Aminopterin produces a sprue-like syndrome in dogs. This syndrome includes diarrhea, peripheral leukopenia, depletion of bone marrow, anorexia, progressive weight loss, dehydration, severe ileitis, and ulcerative colitis with hemorrhagic diarrhea.
    1) This ends with terminal collapse, coma, and death (Phillips & Thiersch, 1949).
    B) Chronic intoxication in dogs produces progressive liquefaction of the bone marrow, with corresponding changes in the blood, and some damage to the lymphoid tissue (Sollman, 1957).
    11.1.6) FELINE/CAT
    A) Teratogenicity studies in cats given aminopterin 0.1 mg/kg in a single oral dose on day 12, 14, and 16 of gestation were inconclusive (Khera, 1976). Of the 4 live fetuses aborted, 3 were malformed (Khera, 1976).
    11.1.9) OVINE/SHEEP
    A) Osteoporotic fractures in prenatal lambs were associated with aminopterin administration during gestation (James, 1972).

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