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March 23, 2007
Aminopterin Toxicity

March 24, 2007 - 3 AM ET
This document was generated rapidly after the announcement of aminopterin (a rodenticide) being highly suspected as the contaminant in the recalled pet foods produced by Menu Foods.

While there is relatively little information currently available, we believe this to be accurate and may help you with your patients.

With the help of the VIN community, we will update and refine this information. Please provide feedback and suggestions in this Message Board Discussion. Thanks!

Please read the Menu Foods VIN Community Update for additional information.
Please read the Menu Foods Renal Function Monitoring document for additional information.

What is Aminopterin?
Aminopterin (4-aminopteroic acid) is an inhibitor of folic acid synthesis. It was originally used as an antineoplastic agent in the late 1940s, but was superseded by methotrexate, a related, but less toxic, inhibitor of folic acid synthesis.

What is aminopterin used for today?
While it is currently undergoing renewed clinical interest as an antineoplastic, it is predominantly used as a rodenticide in some countries. This use is not legal in the United States.

What toxicity is associated with aminopterin?
The toxic side effects listed below are extrapolated from those reported for methotrexate. We suspect that they apply to aminopterin, but readers should remember that we do not know this for certain.

At high doses, methotrexate results in deposition of 7-hydroxymethotrexate in the renal tubules, resulting in crystalluria and acute renal failure. These precipitates are much more likely in the tubules in acidic urine.

Aminopterin may also cause direct tubular damage (not very well studied) in the kidneys in addition to the precipitation described above for methotrexate (Personal communication, Louis-Philippe de Lorimier, DVM, DACVIM (Oncology)).

Methotrexate and aminopterin also inhibit DNA/RNA synthesis by inhibiting folate synthesis (competitive reversible inhibition of dihydrofolate reductase). Folate is required for thymidine synthesis (one of the nucleoside precursors of DNA). This leads to cell death of rapidly-dividing cells (blood cells, gastrointestinal cells).

Since aminopterin is new to all of us, we are going forward on the assumption that aminopterin toxicity and its management is analogous to methotrexate toxicity.

How is aminopterin toxicity treated?
The nephrotoxicity is treated with aggressive hydration and diuresis to dissolve and remove the crystals from the tubules.

Dr. Louis-Philippe de Lorimier (LP) also suggests that urine alkalinization is important (especially soon after exposure). He recommends the use of sodium bicarbonate IV, with a therapeutic goal of a urine pH above 7.5, which will decrease the precipitation in the tubules.

Because it is acidifying, physiologic saline may not be the best choice of crystalloid for these patients. However, if that is the only IV fluid available, it is better than nothing.

Based upon reports in humans and reports by colleagues in this current situation, at least partial renal recovery can be anticipated in many cases.

Bone-marrow suppression (myelosuppression) is a concern with any folic acid inhibiting agent. A small number of VINners have reported anemia in patients exposed to the affected foods.

Thus far, there are no reports of thrombocytopenia or leukopenia, but these effects may not be apparent until later in the disease process.

At this point, it is impossible to say if this potential effect needs to be addressed. Changing the food fed and removing the insult is the most important step, and may be adequate.

Folinic Acid (not FOLIC ACID), leucovorin, can be considered prophylactically, to prevent or minimize myelosuppression and mucositis. Antibiotic therapy may be necessary in cases of severe neutropenia. Folinic acid (leucovorin) doses are 1 mg/kg/day, orally.

Gastrointestinal damage may result in endotoxemia, diarrhea, and vomiting. Supportive therapy is indicated if these signs are observed in an exposed patient.

How should I monitor patients exposed to or affected by the contaminated foods?
Renal function monitoring is detailed in the Renal Function Update.

Based on the known effects of aminopterin and methotrexate, patients should be monitored for neutropenia, thrombocytopenia, and anemia with routine blood tests. Currently, no reports of myelosuppression have been noted, so we are going to have to use our best judgment. With routine antineoplastic therapy, weekly monitoring of CBC is recommended.

Until further information is available, we should, as a community, remain aware that this may be observed in these patients -- but that no further recommendations can be made at this time. It might be prudent to consider monitoring patients who have recovered from (or are currently presenting with) renal insufficiency, as these are most likely to have received larger doses of aminopterin.

Owners should be advised to monitor for bruising, bleeding, melena, hematochezia, or persistent malaise that may indicate endotoxemia or septicemia.

Additional Resources

More information on aminopterin can be found here.

More information on methotrexate can be found here.


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