Methotrexate toxicity

Leucovorin (folinic acid) - enzyme cofactor for thymidylate synthase rescues from methotrexate toxicity potentiates cytotoxicity of fluoro— pyrimidines -occasional nausea -skin rash -headache -rare allergic reactions... 

III. A nine-year-old boy is diagnosed with acute lymphoblastic leukemia. He is maintained on methotrexate. A recent platelet count is below normal, and a stool guaiac is 4+. Which of the following agents should be administered to counteract methotrexate toxicity ... 

Ulrich, C.M., et al., "Pharmacogenetics of Methotrexate Toxicity Among Marrow Transplantation Patients Varies with the Methylenetetrahydrofolate Reductase C677T Polymorphism," Blood, 98, 231-234 (2001). 

Folate deficiency Folate deficiency states may increase methotrexate toxicity. Benzyl alcohol Methotrexate sodium for injection contains the preservative benzyl alcohol and is not recommended for use in neonates. 

Ulrich CM, Yasui Y, Storb R et al. Pharmacogenetics of methotrexate toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001 98 231-234. 

Methotrexate [NE] Possibly increased methotrexate toxicity (especially with anticancer doses of methotrexate). 

Methotrexate [P] Decreased renal methotrexate excretion possible methotrexate toxicity. 

A number of toxic effects on the blood have been documented, including agranulocytosis caused by chlorpromazine, hemolytic anemia caused by methyldopa, and megaloblastic anemia caused by methotrexate. Toxic effects on the eye have been noted and range from retinotoxicity caused by thioridazine to glaucoma caused by systemic corticosteroids. 

METHOTREXATE PROCARBAZINE t risk of renal impairment if methotrexate infusion is given within 48 hours of procarbazine administration. Also t risk of methotrexate toxicity, particularly to the kidneys Procarbazine has a transient effect on the kidneys, and this will delay the renal elimination of methotrexate Do not start methotrexate infusion less than 72 hours after the last dose of procarbazine. Hydrate patients aggressively (plenty of oral fluids or intravenous fluids), alkalinize the urine to pH>7 and closely monitor renal function, e.g. blood urea and creatinine, before and after methotrexate infusion until methotrexate blood levels are <0.05 xmol/L... 

For a displacement interaction to become clinically important, a second mechanism usually operates sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules the result is serious methotrexate toxicity. 

Cytotoxics renal tubular excretion of methotrexate is reduced by competition with NSAIDs, with risk of methotrexate toxicity (low-dose methotrexate given weekly avoids this hazard). 

Cassano WF. Serious methotrexate toxicity caused by interaction with ibuprofen. Am J Pediatr Hematol Oncol 1989 ll(4) 481-2. 

Chatham WW, Morgan SL, Alarcon GS. Renal failure a risk factor for methotrexate toxicity. Arthritis Rheum 2000 43(5) 1185-6. 

Beta-lactams are weak organic acids that compete with the renal tubular secretion of methotrexate and its metabolites and reduce their clearance, leading to methotrexate toxicity (250,251). Consecutive aplastic crises have been described, particularly in patients with impaired... 

The authors suggested that methotrexate toxicity was precipitated by co-trimoxazole. 

A. Rescues normal cells like it does for methotrexate toxicity... 

Methotrexate + salicylates Potentiation of methotrexate toxicity Displacement of methotrexate from protein binding sites Owing to severity of methotrexate toxicity, salicylates should not be given to patients receiving methotrexate... 

Methotrexate + sulfonamides Potentiation of methotrexate with high risk of toxicity Displacement from protein binding (sulfafurazole reduces methotrexate binding from 70% to 28%) Owing to severity of methotrexate toxicity, sulfonamides that are protein-bound should never be administered... 

Fisher MC, Cronstein BN (2009) Metaanalysis of methylenetetrahydrofolate reductase (MTHFR) polymorphisms affecting methotrexate toxicity. J Rheumatol 36 539-545... 

Lopez-Lopez E, Martin-Guerrero I, Ballesteros J et al (2013) A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric lymphoblastic leukemia. Pharmacogenomics J 13(6) 498-506... 

The rescue of normal, but not tumor, cells from methotrexate toxicity by folinic acid is partly explained by differences in membrane transport. For example, osteogenic sarcoma cells (which do not respond to conventional doses of methotrexate treatment) are not rescued by folinic acid administered after methotrexate, presumably owing to the absence of transport sites for folinic acid in the neoplastic cells. The therapeutic effects of administration of methotrexate and rescue with folinic acid are superior to those of methotrexate alone. Resistance to methotrexate can develop from increased activity of dihydrofolate reductase, synthesis of an enzyme having a lower affinity for the inhibitor, decreased transport of the drug into tumor cells, decreased degradation of the reductase, and genetic amplification of the gene for dihydrofolate reductase. 

Because it is a folic acid antagonist, methotrexate can induce a folic acid deficiency. This deficiency is thought to be partly responsible for methotrexate toxicity, and supplementation with folic acid has been shown to alleviate some adverse effects. Addition of folic acid to a methotrexate regimen for rheumatoid arthritis does not compromise drug efficacy. ... 

Drug interactions may potentiate methotrexate toxicity. For example nonsteroidal anti-inflammatory drugs can reduce renal clearance of methotrexate, resulting in toxic levels. Table 96-5 lists selected drugs that interact with, and increase toxicity of, methotrexate. 

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