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PubMed2003

Case-crossover and case-time-control designs in birth defects epidemiology.

The case-crossover and the case-time-control designs can be used to evaluate the effect of intermittent exposures on the risk of acute events. To explore how birth defects epidemiology could benefit from these approaches, the authors compared them with a traditional case-control study design that evaluated the association between use of folic acid antagonists during the second and third pregnancy months and the risk of cardiovascular defects. Among 3,870 cases and 8,387 control infants in the Slone Epidemiology Center Birth Defects Study (1976-1998), the odds ratio was 2.3 (95% confidence interval (CI): 1.4, 3.9). The case-crossover approach compared folic acid antagonist use between the 2-month embryologically sensitive period (case window) and the 2 months preceding the last menstrual period (control window) among mothers of case infants (odds ratio = 1.0, 95% CI: 0.5, 2.0). Although it controls between-person confounding and avoids issues of control selection, this design may be biased by time trends of exposure prevalence during pregnancy. The case-time-control design, which adjusts for exposure time trends under certain assumptions, yielded an odds ratio of 2.9 (95% CI: 1.2, 7.2), but it requires controls. In the presence of gestational time trends of exposure, the new designs do not offer clear advantages over the case-control design.

Case-Control Studies↗
PubMed2006

A tribute to Sidney Farber-- the father of modern chemotherapy.

Sidney Farber, world-renowned paediatric pathologist, made major contributions to his field but is acknowledged as the father of the modern era of chemotherapy. He recognised that folic acid stimulated leukaemic cell growth and enhanced disease progression. He hypothesised that folic acid antagonists would inhibit or arrest the proliferation of cancer cells. His landmark study, published in 1948, demonstrated that a number of folic acid antagonists, including 4-aminopteroyl-glutamic acid (aminopterin) produced temporary remissions in children with acute undifferentiated leukaemia. These observations lead to the development and use of other chemotherapeutic agents, either singly or, more effectively, in combination for treating childhood and adult malignancies. He introduced actinomycin D for the treatment of metastatic and localised Wilms tumour. Under his guidance and leadership, both the 'Jimmy Fund', one of the first comprehensive paediatric oncology treatment centres, and the Children's Cancer Research Foundation, which later became the Dana-Farber Cancer Institute, were founded.

Hematology↗
PubMed1983

[Vitamin B12 as a regulator and methotrexate as an antagonist of folic acid metabolism. Pathophysiologic and clinical aspects].

Biochemical investigations show a decreased bioavailability of 5-methyl-tetrahydrofolic acid in vitamin B12 deficient human cell cultures and bone marrow cells. Tetrahydrofolic acid cannot be liberated from its storage form. This so-called methyl-folate-trap results in a functional folic acid deficiency which is the pathogenetic principle of the defect in the cell proliferation in patients with vitamin B12 deficiency. This knowledge of biochemical mechanisms leads to the identification of rare disorders in the metabolism of vitamin B12 and folic acid. After methotrexate treatment a rescue effect with its antidote Leucovorin can only be achieved, if the ratio antidote: methotrexate is at least 10:1. This ratio is important in cell cultures as well as in bone marrow cells in vivo. The results lead to a formula for the calculation of the optimal dosis to reach a secure rescue for individual patients after high-dose methotrexate treatment. This makes the high-dose methotrexate regimen a treatment modality for malignant tumors without any side effects.

DNA↗
PubMed1989

The folate antagonist, methotrexate, is a potent inhibitor of murine and human cytomegalovirus in vitro.

Cytomegalovirus (CMV) is a major source of morbidity for immunocompromised patients, such as AIDS patients. The folic acid antagonists have not been explored as potential antiviral agents against CMV. We examined the effects of methotrexate, compared to acyclovir and ganciclovir, on both murine CMV (MCMV) and human CMV (HCMV) in vitro. Using a plaque assay in mouse embryo cells or human foreskin fibroblasts for MCMV and HCMV respectively, we found that methotrexate, in micromolar concentrations, was a potent inhibitor of both viruses. This effect was due to folic acid antagonism since folinic acid abrogated the antiviral effect of methotrexate, but not ganciclovir. Cellular toxicity due to methotrexate appeared insufficient to account for the antiviral effects. The ability of methotrexate to inhibit CMV in vivo merits exploration.

Acyclovir↗
PubMed1988

In vitro susceptibility of Trichomonas vaginalis to 50 antimicrobial agents.

We determined the susceptibilities of five strains of Trichomonas vaginalis, one of which was metronidazole resistant, to 50 antimicrobial agents. For the metronidazole-susceptible strains, the most active agents were metronidazole, tinidazole, mebendazole, furazolidone, and anisomycin. Against the resistant strain mebendazole, furazolidone, and anisomycin were the most active. Antifungal agents, beta-lactams, macrolides, aminoglycosides, and folic acid antagonists were ineffective against all strains.

Animals↗
PubMed2003

Findings on potential teratogens from a case-control study in Western Australia.

OBJECTIVES: To examine, in Western Australian women, pregnancy use of drugs that have been found to be associated with birth defect risks in other studies. DESIGN: Data were used from a retrospective study of birth defects in which mothers were sent questionnaires asking about a variety of pregnancy events and exposures, including specific questions on medication use. POPULATION: Case subjects were fetuses or infants with structural birth defects born in Western Australia from 1997 to 2000, identified from the Western Australian Birth Defects Registry. Control subjects were infants without birth defects, randomly selected from the Western Australian Midwives' Notification System. MEASURES: First trimester uses of corticosteroids, medications that antagonise folic acid metabolism, and vasoactive drugs were compared between case and control mothers. RESULTS: The mothers of 2.5, 2.4, and 1.9% of controls, cases, and oral cleft cases, respectively, reported corticosteroid use. The mothers of 0.6% of controls and 1.4% of cases used a folic acid antagonising medication, yielding an odds ratio of 2.3 (95% confidence interval, 0.58-9.4). The mothers of 4.5% of controls and 7.1% of cases used a vasoactive drug (pseudoephedrine, aspirin, ibuprofen, amphetamine, cocaine, or ecstasy). Cigarette smoking is also vasoactive. For exposure to both a vasoactive drug and cigarette smoking, the birth defect risk was 3.0 (0.92-9.6). CONCLUSIONS: There was no difference in corticosteroid use between case and control mothers, although the number of exposed subjects was small. Odds ratio estimates for folic acid antagonists and vasoactive agents support previously reported associations, but they were not statistically significant.

Abnormalities, Drug-Induced↗
PubMed1983

Effect of a synthetic folic acid analogue, 9-methyl-pteroylglutamic acid, on fetal chondrogenesis: ultrastructural observations.

Maternally administered folic acid antagonists (x-methyl-PGA and 9-methyl-PGA) are known to produce various skeletal malformations in the neonate. These defects are thought to be due in part to abnormal metabolism and/or deposition of various extracellular matrix components, i.e., collagen and glycosaminoglycans. Experimental reduction of glycosaminoglycan biosynthesis in vitro has been shown previously to alter the spatial orientation and normal pattern of collagen fibrillogenesis. Furthermore, dietary withdrawal of folic acid concomitant with maternal administration of 9-methyl-PGA has been shown to result in abnormal collagen, uronic acid, and hexosamine metabolism by fetal limbs. In the present study pregnant rats were exposed to a transitory folic acid deficiency from day 11 to 14 of gestation and fetal tibias (mid-diaphyseal region) were examined with the electron microscope on day 18 of gestation. Although we were unable to ascertain any aberrant patterns of fibrillogenesis and orientation with respect to collagen, this particular teratogenic regimen resulted in an altered pattern of chondrocyte development when observed at the ultrastructural level.

Abnormalities, Drug-Induced↗
PubMed1986

Developmental regulation of the pathways of folate-receptor-mediated stimulation of cAMP and cGMP synthesis in Dictyostelium discoideum.

Recently, we demonstrated the presence of multiple folate-binding sites on the cell surface of Dictyostelium discoideum. These sites were divided into two major classes, with different ligand specificities (A and B). Each major class consists of several interconvertible subtypes. In the present report, the ability of 13 folate analogs to activate both adenylate and guanylate cyclase in pre- as well as postaggregative cells is examined. The patterns of correlation between binding and activation data indicate that guanylate cyclase activation is mediated by the B-sites in both developmental stages (P less than 0.001). In postaggregative cells, adenylate cyclase also seems to be activated by the B-sites (P less than 0.001). In contrast, adenylate cyclase activation in preaggregative cells was well correlated with the specificity of A-sites (P less than 0.01). Remarkably, the potencies of activation were less affected by molecular modifications than the binding affinities were, as suggested by a slope of 0.4 in a plot of K0.5 values of activation vs. binding. This observation argues against the existence of a transduction mechanism in which the response is proportional to receptor occupancy. For the B-receptor, however, the degree of receptor occupancy appears to determine the response. The existence of folic acid antagonists is demonstrated, some of which are specific for either A-sites coupled to adenylate cyclase or for B-sites coupled to guanylate cyclase.

Adenylyl Cyclases↗
PubMed1999

Developmental delay in fetal aminopterin/methotrexate syndrome.

Maternal exposures to aminopterin and methotrexate have been associated with a pattern of malformation which includes prenatal-onset growth deficiency, severe lack of ossification of the calvarium, hypoplastic supraorbital ridges, small, low-set ears, micrognathia, and limb abnormalities. We report on a patient whose mother received methotrexate during the first trimester of pregnancy and who, in addition to the structural anomalies typical of maternal methotrexate exposure, has significant developmental delay. This is the third patient exposed to folic acid antagonists with mental retardation, providing further evidence that developmental delay is one feature of fetal aminopterin-methotrexate syndrome. Therefore, it is recommended that formal developmental testing be performed in all patients prenatally exposed to methotrexate.

Abnormalities, Drug-Induced↗
PubMed2002

Detection and characterization of mechanisms of action of aneugenic chemicals.

A comprehensive evaluation of the genotoxic potential of chemicals requires the assessment of the ability to induce gene mutations and structural chromosome (clastogenic activity) and numerical chromosome (aneugenic activity) aberrations. Aneuploidy is a major cause of human reproductive failure and an important contributor to cancer and it is therefore important that any increase in its frequency due to chemical exposures should be recognized and controlled. The in vitro binucleate cell micronucleus assay provides a powerful tool to determine the ability of a chemical to induce chromosome damage. The application of an anti-kinetochore antibody to micronuclei allows their classification into kinetochore-positive and kinetochore-negative, indicating their origin by aneugenic or clastogenic mechanisms, respectively. The availability of chromosome-specific centromere probes allows the analysis of the segregation of chromosomes into the daughter nuclei of binucleate cells to evaluate chromosome non-disjunction. Quantitative relationships between the two major causes of aneuploidy, chromosome loss and non-disjunction, can be determined. The mechanisms leading to chromosome loss and non-disjunction can be investigated by the analysis of morphological and structural changes in the cell division apparatus by the application of specific stains and antibodies for various cell division components. We illustrate such analyses by the demonstration of the interaction of the monomer bisphenol-A with the centrosome of the mitotic spindle and the folic acid antagonist pyrimethamine with the centromeres of chromosomes. Both types of modifications lead to the induction of aneuploidy in exposed cells. Our studies also implicate the products of the p53 and XPD genes in the regulation of the fidelity of chromosome segregation at mitosis.

Aneuploidy↗
PubMedDate not supplied

[Experimental study of the myelotoxic effect of tomizine].

In tests conducted on 220 rats with transplantable sarcoma M-1 and intact animals acute toxicity, antineoplastic effect and the action on the blood system of tomizine, a new neoplastic drug of the group of the folic acid antagonists, were studied. Investigation involved a single intraperitoneal injection of the drug in DL50/30 and MTD. The compound is shown to exert an inhibiting action on the development of sarcoma M-1 and lengthens the survival of the tumour-stricken animals, without producing any pronounced myelotoxic effect. The disclosed shifts on the level of the periphedal blood and marrow were short-lived and concerned mainly the erythroid germ cells.

Anemia, Aplastic↗
PubMed1999

Population pharmacokinetics of methotrexate in the guinea pig.

The population pharmacokinetics of an antitumoral and antiinflammatory agent, methotrexate (MTX), a folic acid antagonist, was studied in guinea pigs. Animals received an acute intraperitoneal injection of 0.25, 1 or 5 mg/kg MTX. Blood sampling was carried out for 12 hrs. after MTX administration and plasma drug concentrations were measured by fluorescence polarization immunoassay. The pharmacokinetic (PK) parameters were computed using the bayesian population model. MTX reached the level of detection at 3 hrs. for the animals injected with the lowest dose (0.25 mg/kg), at 3.5 hrs. for those animals which had the intermediate dose (1 mg/kg) and more than 6 hrs. for animals having received the highest dose (5 mg/kg). Each kinetic parameter (half life, total clearance - CLt, volume of distribution at steady state - VDSS, mean residence time - MRT - and area under curve - AUC) didn't show any significant difference between doses. MTX kinetic was linear for the first two doses (0.25 and 1 mg/kg MTX) and non-linear thereafter. MTX presented a one compartment distribution.

Animals↗
PubMed1996

A risk-benefit assessment of methotrexate in corticosteroid-dependent asthma.

Methotrexate is a folic acid antagonist with proven anti-inflammatory properties. This originally led to its use in the therapy of some rheumatic and dermatological inflammatory disorders and, since the early 1980s, as a corticosteroid-sparing agent in the therapy of bronchial asthma. Although the exact anti-inflammatory mechanism is not known, it appears that in some patients with severe corticosteroid-dependent bronchial asthma, a reduction of at least 50% in the maintenance corticosteroid dosage can be achieved. Controversies regarding methotrexate efficacy may be a result of the small size and heterogeneity of the patient populations studied and the variable definition of corticosteroid "dependence'. Although the potential for serious short and long term adverse effects resulting from methotrexate therapy cannot be ignored, overall, methotrexate appears to be well tolerated at low dosages. Hepatic and pulmonary toxicity are the main adverse effects of concern. The "lesser evil' approach is logical, but it is imperative to administer the drug for at least 3 months to adequately assess its efficacy in a specific patient.

Adolescent↗
PubMed1999

Pediatric case of accidental oral overdose of methotrexate.

Methotrexate is a chemotherapy antimetabolite, folic acid antagonist, that inhibits the enzyme dihydrofolate reductase resulting in decreased levels of tetrahydrofolate in the cells. This in turn blocks synthesis of thymidylate, a nucleotide necessary for DNA synthesis. It is readily absorbed from the gastrointestinal tract. Toxicity from overdose can affect multiple organ systems including bone marrow, liver, intestinal tract, kidneys, lungs, skin, and blood vessels, resulting in death in severe cases. Methotrexate is widely used to treat neoplastic disease, dermatologic disorders (psoriasis), and rheumatologic disorders (severe rheumatoid arthritis). As its indications for use increase, more accidental overdoses can be expected. We present the treatment and clinical course of one such case, that of a 2-year-old who accidentally took her grandmother's arthritis pills. Her initial serum level was 10 times greater than that needed to cause toxicity. She was treated with gastric lavage, activated charcoal, leucovorin rescue, and ICU admission. Her clinical course was unremarkable, and the only evidence of toxicity was a mild elevation in a liver-associated enzyme that resolved without any clinical sequela. Leucovorin at a dose equal to or greater than the possible ingestion should be given as soon as possible in methotrexate overdoses.

Antidotes↗