<prompt> Which of the following is given to prevent methotrexate toxicity?MESNAFlumazenilFomipezoleCalcium leucovorin  <response>: Ans. d Calcium leucovorin Ref. Harrison 18th p 476, 607 Methotrexate inhibits dihydrofolate reductase, which regenerates reduced folates from the oxidized folates produced when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates, cells die a thymineless death. N-5 tetrahydrofolate or N-5 formyltetrahydrofolate leucovorin can bypass this block and rescue cells from methotrexate, which is maintained in cells by polyglutamylation.METHOTREXATE - Side Effects: In addition to bone marrow suppression and mucosal irritation, methotrexate can cause renal failure itself at high doses owing to crystallization in renal tubules; therefore high-dose regimens REQUIRE ALKALINIZATION OF URINE with increased flow by hydration.6 Less frequent adverse effects include reversible increases in transaminases and hypersensitivity-like pulmonary syndrome. Chronic low-dose methotrexate can cause hepatic fibrosis. When administered to the intrathecal space, methotrexate can cause chemical arachnoiditis and CNS dysfunction. Trimetrexate is a methotrexate derivative that is not polyglutamylated and does not use the reduced folate carrier. The effects of folate antagonists that inhibit dihydrofolate reductase can be counteracted by folinic acid 5-formyl tetrahydrofolate in a dose of 100 to 200 mgd, which circumvents the block in folate metabolism by providing a form of folate that can be converted to 5,10-methylene THF.MethotrexateAntimetabolite A folic acid analog that inhibits dihydrofolate reductase; decreased dTMP levels hinder DNA and thus protein synthesis S-phase specificNeoplastic indications: leukemia, lymphomas, breast cancer, choriocarcinomaNonneoplastic indications; rheumatoid arthritis, psoriasis, termination of pregnancy e.g., ectopic Toxicities: suppresses bone marrow reversibly; folinic acid leucovorin is used to rescue; fatty change in liver 