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At least 289 records · Page 16Linked to original sources
PubMed1998

Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention.

OBJECTIVE: To determine the effect of longterm methotrexate (MTX) therapy and folic acid supplementation on folate nutriture and homocysteine levels in patients with rheumatoid arthritis. METHODS: A double blind, placebo controlled trial lasting one year was conducted at one academic medical center. A total of 79 patients taking low dose MTX were followed up to one year. The patients were randomized to receive placebo or 5 or 27.5 mg folic acid supplementation per week. RESULTS: Plasma and erythrocyte folate levels and plasma homocysteine levels were determined. The folate nutriture of patients taking low dose MTX declined without folic acid supplementation. Plasma homocysteine levels increased significantly over a one year period in the placebo group. Low folate nutriture and hyperhomocysteinemia occurred with greater frequency in the placebo group than in the folic acid supplemented groups. CONCLUSION: For longterm, low dose MTX therapy, there are now at least 3 reasons to consider supplementation with folic acid (a low cost prescription): (1) to prevent MTX toxicity, (2) to prevent or treat folate deficiency, and (3) to prevent hyperhomocysteinemia, considered by many investigators to be a risk factor for cardiovascular disease.

Adult↗
PubMed1998

Nonpolyglutamatable antifolates as inhibitors of thymidylate synthase (TS) and potential antitumour agents.

Thymidylate synthase (TS), an enzyme that catalyses the conversion of dUMP to dTMP, has been the focus of interest as a target in cancer chemotherapy for more than two decades. Over the last 10 years much research has been devoted to the design and development of nonpolyglutamatable inhibitors of TS as antitumour agents, mainly to over-come resistance due to unfavourable expression of folylpolyglutamate synthetase (FPGS). Lipophilic inhibitors of the enzyme were expected not to depend on the reduced folate carrier transporter (RFC) for cellular uptake, thus avoiding resistance due to an impaired RFC. Compounds of this type can be classified in three groups: A: nonclassical lipophilic inhibitors of TS, mainly folate-based analogues lacking the glutamate side chain; B: folate-based analogues in which the glutamate side chain has been modified in such a way that polyglutamation is precluded; and C: nonpolyglutamatable glutamate-containing inhibitors of TS. Compounds of group A included 5- or 6-substituted quinazolin-4-ones, benzo[flquinazolines, imidazotetrahydroquinoline- and benz[cd]indole-based inhibitors. The second group is mainly related to a series of g-linked dipeptide derivatives of ICIl98583, or analogues of this inhibitor where the glutamate residue was replaced with a range of a-amino acids. The third group is concerned with some 7-substituted derivatives of ICI198583 and the pyrrolo[3, 2-d]pyrimidine-based inhibitor 175. A large number of structurally diverse nonpolyglutamatable inhibitors of TS were synthesised some of which were potent inhibitors of the enzyme (human or E. coli) and in vitro cell growth. Three compounds, i.e. 49 (AG 337), 83 (AG 331), 123 (ZD9331) have reached the stage of clinical evaluation.

Antimetabolites, Antineoplastic↗
PubMed1964

INSECT FERTILITY: INHIBITION BY FOLIC ACID DERIVATIVES.

Folic acid antagonists inhibited oviposition by screw-worm flies [Cochliomyia hominivorax (Coquerel); Diptera: Calliphoridae]. Fertility was unaltered when sufficient folic acid was administered simultaneously, or it was partly restored spontaneously about 2 weeks after treatment. Folic acid antagonists principally affected only maturing eggs at any age, rather than those already matured.

Aminopterin↗
PubMed1985

Drugs and folate metabolism.

Folates are a group of compounds which are required in the diet and are important in DNA, amino acids and possibly also amine metabolism. The biologically active folates are in the tetrahydro form. Tetrahydrofolates are produced from unreduced dietary folates by the enzyme dihydrofolate reductase. A number of drugs such as aminopterin, methotrexate (amethopterin), pyrimethamine, trimethoprim and triamterene act as folate antagonists and produce folate deficiency by inhibiting this enzyme. With other drugs which produce low serum and tissue concentrations of folate such as anticonvulsants, antituberculosis drugs, alcohol and oral contraceptives, the mechanism of this effect is uncertain. Possible mechanism include reduced absorption, prevention of release of folate from tissue stores, altered plasma protein binding, or increased folate metabolism in the liver. Treatment with folic acid antagonists such as methotrexate readily causes megaloblastic anaemia; this can be prevented by therapy with folinic acid (5-formyltetrahydrofolate). The role of other drugs in producing megaloblastic anaemia is less certain, e.g. it occurs in less than 0.75% of patients receiving anticonvulsants. The possible neurological and psychiatric effects of folate deficiency are also uncertain. However, in patients with folate deficiency who have neuropsychiatric symptoms, neuropathy or myelopathy, and normal vitamin B12 levels, it may be of value to try therapy with folic or folinic acid.

Amines↗