Antifolates toxicity

Fohc acid is safe, even at levels of daily oral supplementation up to 5—10 mg (97). Gastrointestinal upset and an altered sleep pattern have been reported at 15 mg/day (98). A high intake of foHc acid can mask the clinical signs of pernicious anemia which results from vitamin deficiency and recurrence of epilepsy in epileptics treated with dmgs with antifolate activity (99). The acute toxicity (LD q) is approximately 500 and 600 mg per kg body weight for rats and mice, respectively (100). 

The dmgs known as antifolates act as effective blood schizonticides. Unfortunately, the parasites readily develop resistance to them. Most antifolates show poor oral tolerance, absorption, and host toxicity. They fall into two types depending on the mechanisms by which they operate. 

Methotrexate -antifolate antimetabolite cell cycle dependent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hepatotoxicity—more common in high-dose therapy -CNS toxicity—dizziness, malaise, blurred vision, encephalopathy -nephrotoxicity—including acute renal failure, particularly at high doses... 

Trimetrexate -antifolate antimetabolite -bone marrow suppression -mucocutaneous effects (mucositis, stomatitis) -nausea and vomiting -fever -maculopapular rash—usually self-limited -anorexia, malaise -above toxicities increased in patient with hypoalbuminemia (<3.5)... 

Folic acid antagonist overdosage In the treatment of accidental overdosages of folic acid antagonists, administer leucovorin as promptly as possible. As the time interval between antifolate administration (eg, methotrexate) and leucovorin rescue increases, leucovorin s effectiveness in counteracting toxicity decreases. 

METHOTREXATE ANAESTHETICS-NITROUS OXIDE t antifolate effect of methotrexate t toxicity of methotrexate Nitrous oxide is usually used for relatively brief durations when patients are anaesthetized, and hence this risk during anaesthesia is minimal. However, nitrous oxide may be used for analgesia for longer durations, and this should be avoided... 

METHOTREXATE ANTIMALARIALS -PYRIMETHAMINE t antifolate effect of methotrexate Pyrimethamine should not be used alone and is combined with sulfadoxine. Pyrimethamine and methotrexate synergistically induce folate deficiency Although the toxic effects of methotrexate are more frequent with high doses of methotrexate, it is necessary to do an FBC, liver and renal function tests before starting treatment even with low doses, repeating these tests weekly until therapy is stabilized and thereafter every 2-3 months. Patients should be advised to report symptoms such as sore throat and fever immediately, and also any gastrointestinal discomfort. A profound drop in white cell count or platelet count warrants immediate stoppage of methotrexate therapy and initiation of supportive therapy... 

In rabbits,, 7-dihydroxy deriv. is major metab. Metab. is less toxic in mice than parent cpd. and has lower antifolic acid activity this may explain resistcince of rabbit to cytotox. of methotrexate (63). 

Thus, a large number of substances have been tested as inhibitors for the steps in purine and pyrimidine metabolism (Cory, in Devlin, 1986, p. 674 0. Inclnded are both synthetic compounds and compounds isolated from plants, bacteria, fungi, etc. The substances may be further classed as glutamine antagonists, antifolates, and antimetabolites. Whereas the first-mentioned substances are toxic in the extrane, the latter two classifications have been of main concern although they are toxic enough in their own right. 

Given that the antifolates enter cells by a nonconcentrating RFC transport system, attaining 99.95% inhibition of DHFR would be virtually impossible without also attaining highly toxic or even lethal blood levels of the antifolate. 

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