Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013911 (emaciation)
 1,059 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trimetrexate is a nonclassical folate antagonist that is active against a number of experimental murine and human tumor cell lines. To assess its toxicity, rats were administered single or repeated (daily x5) doses by either the oral or the intravenous route. Oral doses were 0, 90, 180, 295, and 375 mg/kg (single dose) and 0, 32, 65, and 80 mg/kg (daily x5). Intravenous doses were 0, 6, 20, and 60 mg/kg (single dose) and 0, 10, 20, and 30 mg/kg (daily x5). In the oral studies, signs of toxicity first appeared 2 to 3 days after initiation of dosing. Clinical signs included hypoactivity, diarrhea, urine scald, rhinorrhea, emaciation, and death. Significant pathologic findings were degenerative enteropathy in small and large intestines, bone marrow hypocellularity, decreased WBCs (neutrophils, lymphocytes), generalized lymphoid depletion, and testicular tubular degeneration. Except for the testicular changes, these effects were most severe in animals dosed at 65 and 80 mg/kg in the oral x5 study (65-70% mortality). Repeated oral doses at 32 mg/kg and single oral doses through 375 mg/kg caused only mild to moderate effects and less than 5% mortality. In contrast, single intravenous doses at 60 mg/kg resulted in immediate death (20% mortality) due to apparent CNS toxicity. Intravenous doses below 60 mg/kg were essentially asymptomatic. Toxicity in the intravenous studies was limited to decreased WBCs, splenic and thymic lymphoid depletion (repeated dosing), and testicular tubular degeneration and/or atrophy. Except for the testicular lesions, most of the effects in the oral and intravenous studies were reversible within 4 weeks. The results show that the acute toxicity of trimetrexate in rats is somewhat dependent on its route of administration, although the spectrum of effects is qualitatively similar to that observed in other species and with other folate antagonists. The dose-limiting toxicity of trimetrexate in rats common to both routes of administration is myelosuppression.
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PMID:Toxicity of the anticancer folate antagonist trimetrexate in rats. 153 75