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PubMed2002

Inhibitory effects of ascorbic acid and folinic acid on chromosome aberrations induced by pyrimethamine in vitro.

In this study, the anticlastogenic effects of ascorbic acid and the protective effect of folinic acid against the formation of chromosomal aberrations in humans by pyrimethamine were investigated. Pyrimethamine is a folic acid antagonist used for the treatment of malaria and toxoplasmosis. In this study, 18 different healthy people, who do not drink alcohol and are non-smokers, were chosen as an experimental group; 0.025 mg/ml pyrimethamine was given to the lymphocyte culture, which had been prepared with the peripheral blood taken from this group. After that each of the following doses were given to the same culture: 20, 40, and 80 mM of ascorbic acid and 25, 50, and 100 mM of folinic acid. The results of the cytogenetic evaluation showed that the aberrations due to pyrimethamine in the chromosomes were reduced by ascorbic acid and folinic acid significantly, depending on the given dose.

Ascorbic Acid↗

PubMed2003

Successful desensitization to high-dose methotrexate after systemic anaphylaxis.

BACKGROUND: Methotrexate (MTX) is a folic acid antagonist used in high doses as adjuvant chemotherapy for osteosarcoma. It has many known toxicities and has been reported to cause anaphylaxis. We report the first successful desensitization protocol to high-dose MTX. CASE PRESENTATION: The patient is a 22-year-old male with the evaluation of osteosarcoma, T1Gr2NxM0. He received neoadjuvant chemotherapy and later underwent a right above the knee amputation without complication. He was then scheduled to receive adjuvant chemotherapy with high-dose MTX, 12 g/m2 body surface area, followed by leucovorin rescue and ifosfamide. He had an immediate hypersensitivity reaction during the initiation of the MTX infusion with diffuse urticaria, facial swelling, cough, and chest tightness. The infusion was terminated and his symptoms abated. He was later skin tested to confirm allergy to MTX. In order for him to receive the needed chemotherapy, we developed a desensitization protocol that was administered in the intensive care unit. Before the infusion he was pretreated with ranitidine, cetirizine, hydroxyzine, montelukast, and prednisone. He underwent the desensitization without incident on repeated infusions. Serum tryptase levels drawn during the infusions were low, signifying controlled mast cell degranulation. CONCLUSIONS: This case describes the original development of a desensitization protocol to high-dose MTX. The successful development and implementation of this protocol will have impact on patients who have anaphylactic reactions to MTX but require this medication for specific diseases. For patients who suffer from osteogenic sarcoma and have anaphylactic reactions to MTX, this desensitization protocol will allow these patients to continue with needed therapeutic or palliative chemotherapy.

Adult↗

PubMed1989

Mechanism of the induction of the differentiation of HL-60 leukemia cells by antifolates.

The classic inhibitor of dihydrofolate reductase (DHFR), methotrexate (MTX), has been shown to be an effective inducer of the differentiation of HL-60 promyelocytic leukemia cells (Bodner A.J. et al.; J. Natl. Cancer Inst. 67:1025-1030; 1981). We have obtained evidence that induction of the differentiation of these cells by MTX, as well as by other folic acid antagonists, is the result of the effects of these agents on purine and thymine nucleotide biosynthesis. Thymidine (10 microM) completely blocked both the cytotoxicity and induction of differentiation produced by the specific inhibitor of thymidylate synthase (TS), N10-propargyl-5,8-dideazafolic acid (CB-3717). Thymidine also blocked the acute cytotoxicity caused by MTX and trimetrexate (TMQ); the induction of differentiation and the loss of proliferative capacity, however, were only partially prevented by thymidine. Hypoxanthine (100 microM), which completely restored antifolate-depleted purine nucleotide levels, had no effect on either the cytotoxicity or the induction of maturation produced by these agents. The growth inhibitory effects and the induction of differentiation caused by dideazatetrahydrofolic acid (DDATHF), which acts on de novo purine nucleotide biosynthesis rather than on DHFR or TS, was completely prevented by hypoxanthine. Hypoxanthine also completely prevented the inhibition of cellular replication and induction of differentiation by MTX and TMQ when combined with thymidine. The findings suggest that the depletion of intracellular thymine nucleotide levels by the antifolates, MTX, TMQ, and CB-3717 is the primary event involved in the maturation of HL-60 leukemia cells produced by these agents and that maturation occurs concomitantly with a high level of cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗

PubMed2005

Methotrexate for primary biliary cirrhosis.

BACKGROUND: Methotrexate, a folic acid antagonist with immunosuppressive properties, has been used to treat patients with primary biliary cirrhosis. The therapeutic responses to methotrexate in randomised clinical trials have been heterogeneous. OBJECTIVES: To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. SEARCH STRATEGY: Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 2, 2004), MEDLINE (January 1966 to August 2004), EMBASE (January 1980 to August 2004), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Our primary outcomes were mortality and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and hazard ratio (HR) if applicable. Continuous outcomes were reported as weighted mean difference (WMD). We examined intervention effects by using both a random-effects model and a fixed-effect model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS: We identified four trials (370 patients) that compared methotrexate with placebo with or without ursodeoxycholic acid as co-intervention. One additional trial (87 patients) compared methotrexate with colchicine without and later with ursodeoxycholic acid as co-intervention. The methodological quality of the trials was low. We did not find significant effects of methotrexate on pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (WMD - 0.68, 95% CI - 1.11 to - 0.25), the levels of serum alkaline phosphatases (WMD - 0.41, 95% CI - 0.70 to - 0.12) and plasma immunoglobulin M (WMD - 0.47, 95% CI - 0.74 to - 0.20) were significantly lower in the patients receiving methotrexate. AUTHORS' CONCLUSIONS: Methotrexate increased mortality in patients with primary biliary cirrhosis. We do not recommend methotrexate for patients with primary biliary cirrhosis outside randomised trials.

Folic Acid Antagonists↗

PubMed1951