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Results for “FOLIC ACID ANTAGONISTS”

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At least 361 records · Page 20Linked to original sources
PubMed2000

Prenatal methotrexate exposure decreases seizure susceptibility in young rats of two strains.

Effects of prenatal exposure to methotrexate (MTX) administered in Sprague-Dawley (one 5 mg/kg dose of MTX on gestational day 15; E15) or Wistar (one 5 mg/kg dose of MTX on E14 or E15 or two such doses on E15) pregnant rat dams were studied in developing offspring. Young Sprague-Dawley rats were subjected to rapid kindling on postnatal days (PN) 15 and 16, and to flurothyl seizures on PN 15 and PN 30. Offspring of the Wistar strain were tested in flurothyl on PN 30. In Sprague-Dawley rats, prenatal exposure to MTX decreased susceptibility to kindling-induced seizures on PN 15 and to flurothyl-induced clonic seizures on PN 30. In Wistar rats, a single dose of MTX on E15 was ineffective, but two doses significantly decreased susceptibility to flurothyl-induced seizures. Additionally, due to a shorter duration of pregnancy in Wistar rats, exposure to a single dose of MTX on E14 also decreased susceptibility to flurothyl seizures. MTX, as folic acid antagonist, interferes with DNA synthesis. However, unlike other treatments that suppress DNA synthesis (such as methylazoxymethanol exposure or X-ray radiation), MTX exposure results in anticonvulsant effects in surviving offspring. The data suggest that not all prenatal impairments of DNA have proconvulsant features postnatally.

Animals↗
PubMed1984

Sister chromatid exchange frequency and cell cycle kinetics in cancer patients treated with cytostatic drugs.

The ability of various cytostatic drugs to induce sister chromatid exchanges (SCE) and to alter the progression of cells through mitosis was analyzed in lymphocytes cultured from cancer patients following various in vivo chemotherapy treatments. Control individuals exhibited 4.87 +/- 0.08 SCEs per metaphase. Patients being treated with cyclophosphamide (CP), mitomycin C (MMC), and/or cisplatinum (CPT) in combination with other drugs exhibited 3- to 5-fold greater levels of SCEs. Other cytostatic drugs: the plant alkaloids; vincristine (VCR); and homoharringtonine (HHT); the antibiotic, adriamycin (ADM); the folic acid antagonist, methotrexate (MTX); and the nucleotide analogue, dihydroazacytidine (HAC) did not appear to induce SCE levels significantly above controls. Most of the cytostatic drugs used in cancer patients appeared to delay the progression of cells through mitosis. All the drug protocols which included a known DNA-damaging agent induced SCE. There was no relationship between SCE and cell cycle kinetics. Thus, SCE appears to be a sensitive assay for monitoring the in vivo exposure of individuals to genotoxic agents.

Adolescent↗
PubMed1993

Chemical teratogenesis.

This review has briefly summarized what is currently known concerning the mechanisms whereby several groups of chemicals regarded as "recognized" human teratogens elicit their respective teratogenic effects. It is evident that the extent of our understanding of mechanisms for individual chemicals varies dramatically from that of a reasonably good understanding for methotrexate and other folic acid antagonists to that of virtually no understanding for the most widely recognized human teratogen, thalidomide. Even with methotrexate, however, much remains to be learned pertaining to mechanisms--i.e., the critical links in the chain of events between dihydrofolate reductase inhibition and the manifestation of specific abnormalities. Nevertheless, we can take some comfort in being able to say that we understand the primary causative mechanism. For thalidomide, as well as several others the chemical represents both a shame and a challenge--a challenge that should be addressed with our most serious efforts.

Abnormalities, Drug-Induced↗
PubMed1997

Chemical teratogenesis in humans: biochemical and molecular mechanisms.

In this review, an attempt has been made to summarize our current understanding of the mechanisms whereby certain chemicals cause birth defects. The chemicals selected for consideration were those that have been designated as established or recognized human teratogens. It is clear that our current understanding of mechanisms whereby these agents cause teratogenic effects (birth defects) can vary dramatically from one agent to the next. Extremes include the folic acid antagonists, which are now well established as agents that produce birth defects by virtue of potent inhibition of dihydrofolate reductase as a primary biochemical mechanism. An example at the other extreme is ethanol, for which very few definitive statements can be made with regard to teratogenic mechanisms, and the probability exists that a large number of interacting, contributory mechanisms can be invoked. For nearly all chemical teratogens, the critical links in the chains of events between the initial, primary biochemical and molecular mechanistic event (e.g. dihydrofolate reductase inhibition) and the manifestations of specific abnormalities (pathogenic mechanisms) remain to be delineated. This will provide an enormous challenge for investigators for years to come.

Abnormalities, Drug-Induced↗
PubMed1991

The clastogenic effect of pyrimethamine (Daraprim) on human chromosomes in lymphocyte cultures.

In this study the clastogenic effect of pyrimethamine (Daraprim), a folic acid antagonist used for the treatment of toxoplasmosis and malaria on human chromosomes, was investigated. Pyrimethamine was added to in vitro lymphocyte cultures at six different concentrations: 0.05 (normal therapeutic dose), 0.1, 0.2, 0.4, 0.8, and 1.6 mg/ml. No proliferation was observed in any of the cultures containing 1.6 mg/ml pyrimethamine. The results of the cytogenetic evaluations show that the frequency of breaks and gaps increase significantly in dose-dependent manner. Thus, pyrimethamine has a clastogenic effect on human chromosomes.

Adolescent↗
PubMed1989

In vitro secretion of bovine immunoglobulins during pokeweed mitogen or pokeweed mitogen and antigen activation of lymphocytes.

Activation of bovine peripheral blood mononuclear cells (PBM) towards immunoglobulin (Ig) synthesis and secretion was examined in vitro using pokeweed mitogen (PWM) or PWM plus sheep red blood cells (SRBC). Bovine PBM were composed of 7-30% B cells, 25-56% T cells and 1-4% macrophages. Cell density and PWM concentrations were critical parameters for obtaining reproducible maximum lymphocyte proliferation and polyclonal B cell activation. Inclusion of aminopterin, a folic acid antagonist, reduced cellular proliferation and viability but had no apparent effect on the time of appearance of peak proliferation. Co-culture of PBM with SRBC and PWM generated anti-SRBC specific antibodies.

Animals↗
PubMed1983

Frequency of fragile X chromosomes, fra(X), in lymphocytes in relation to blood storage time and culture techniques.

The fra(X) frequencies in metaphases of lymphocytes from seven male patients with X-linked mental retardation and macroorchidism were scored after use of different culture techniques and different times of blood storage. No statistically significant differences were found between the fra(X) rates of lymphocytes grown either in folic acid deficient medium (TC 199) or in medium containing folic acid as well as a folic acid antagonist (methotrexate: MTX, aminopterine: AP). With respect to the effect of the time interval between blood sampling and culture set-up, a statistically significant decrease in the fra(X) frequency was observed in all culture types after 4 or 7 days of blood storage.

Blood Preservation↗
PubMed1979

Effect of liposome-entrapped methotrexate on Ehrlich ascites tumor cells and uptake in primary liver cell tumor.

A therapeutically useful concentration (0,5 mg/ml) of Methotrexate was prepared in negatively charged artificial liposomes (lecithine: cholesterol: dicetylphosphate=5:5:1 molar ratios). Entrapment yield after separation on Sepharose 6B is nearly 100%. In contrast to free Methotrexate the liposome entrapped folic acid antagonist is eliminated only slowly by the kidneys and after intravenous application it is unevenly distributed in the body of mice, the highest concentrations being found in liver and spleen. Daily injections (7.5 mg/kg/day) of entrapped Methotrexate for 5 days into the tail vein of Ehrlich ascites tumor bearing mice reduced both tumor cell count and the production of ascites fluid about fourfold as compared to mice receiving the same dose of Methotrexate in the free form. Six hours after intravenous application of liposome entrapped Methotrexate the tissue concentration in normal liver is ca. 20-fold higher than when the same amount is applied in the free state. On the other hand, only a little uptake of liposome entrapped Methotrexate was detected in the tissue of nitrosamine-induced primary liver tumor when compared to normal liver tissue of rats.

Animals↗
PubMed1978

Role of carbon dioxide in germination of spores of Streptomyces viridochromogenes.

CO2 is required continuously during germination of Streptomyces viridochromogenes spores. Spores incubated in a defined germination medium in the absence of CO2 remain phase bright and do not release spore carbon. In the presence of CO2, the spores initiate germination accompanied by loss of refractility and spore carbon. The CO2 requirement is replaced by oxaloacetate or a mixture of tricarboxylic acid cycle (TCA) intermediates. Labeled CO2 is taken up by germinating spores, and is incorporated into protein and RNA. TCA cycle intermediates and related amino acids contain most of the acid-soluble label following short term exposures of germinating spores to 14CO2. TCA cycle inhibitors repress germination and 14CO2 uptake whereas folic acid antagonists do not. The results indicate that CO2 is incorporated into oxaloacetate which is converted to biosynthetic intermediates required for germination. Operation of the TCA cycle appears to be essential for spore germination. The conclusion is reached that CO2 is required during germination in order to maintain the cycle by an anaplerotic reaction.

Adenosine↗
PubMed1982

The effect of folates on the reflex activity in the isolated hemisected frog spinal cord.

Folates may play a role in epileptic phenomena and may also be involved in synaptic events. Recently methyltetrahydrofolate was found to be a potent competitor for 3H-kainic acid binding sites in the cerebellum. The effects of 1 mM methyltetrahydrofolate (MTHF), 1 mM formyl-tetra-hydrofolate (FTHP) and 1 mM Na-folate (Na-F) were tested on the reflex activity of the isolated hemisected frog spinal cord. MTHF and FTHP were found to have an initial excitatory effect on the evoked ventral root responses. This was followed by a gradual decrease in the amplitudes of the ventral root responses. Sodium folate had only an inhibitory effect on these responses. When the evoked ventral root responses were totally inhibited by the folates the preparations did not respond to any of the following substances: (a) Kainic acid (KA), (b) L-glutamic acid (LG), (c) picrotoxin or (d) strychnine. All the folates had an inhibitory effect on the dorsal root responses. In most preparations neuronal activity was only partially restored by perfusion with normal Ringer solution. When the isolated spinal cords were bathed in either 0,5 mM KA or 1 mM LG similar results were obtained to that found with MTHF and FTHF. Glutamic acid diethyl ester (GDEE, 1 mM), however, yielded similar results to that seen with Na-F. It seems that the glutamates and related substances differ in their ability as neuroexcitants, but all share the common ability to inhibit synaptic activity when nervous tissue is exposed to the substances for long periods. Some of the folates share with KA some degree of neurotoxicity. These experiments could also not point out a separate kainic receptor in the frog spinal cord.

Animals↗
PubMed1984

Clostridium difficile colitis associated with the use of antineoplastic agents.

Eight patients are presented in whom treatment with antineoplastic agents, in particular the folic acid antagonist methotrexate, precipitated Clostridium difficile-related diarrhoea and pseudomembranous colitis. The clinical presentation of these patients was identical to that encountered in patients developing antibiotic associated diarrhoea and colitis. Clostridium difficile-related diarrhoea and colitis should be suspected in any patient developing diarrhoea during the course of anti-neoplastic chemotherapy or within three weeks of its cessation. This complication is effectively treated with oral vancomycin.

Adult↗
PubMed1999

Topical application of methotrexate for inhibition of corneal angiogenesis.

PURPOSE: Methotrexate (MTX) is a folic acid antagonist used in chemotherapy regimens. Additional therapeutic applications have been suggested based on effect as an immuno-modulating drug in systemic rheumatoid disease and associated uveitis. Since chronic inflammatory disease is often associated with a neovascular response, we investigated the use of MTX for treatment of corneal angiogenesis. METHODS: Neovascularizations were induced by fibroblast growth factor in a corneal pocket model. Vessels were examined biomicroscopically. MTX was applied topically to rabbit corneas in a concentration of 0.2 mg/day. MTX level was measured in aqueous humor and plasma. RESULTS: On day 9 the vascularized area was 12.0+/-6.9 mm(2) in control eyes and significantly smaller, 2. 2+/-1.86 mm(2), in treated eyes. Treated animals showed no local side effects such as epithelial defects. Although therapeutic levels were measured in the aqueous humor, MTX could not be detected in the serum of treated animals. CONCLUSION: The antiangiogenic mechanism of MTX might be due to inhibition of both macrophage invasion during early angiogenesis and endothelial cell proliferation. The high levels in the aqueous humor indicate a possible application of topical MTX for inflammations of the anterior segment of the eye.

Animals↗
PubMed2006

L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death.

Methotrexate (MTX), a folic acid antagonist widely used for the treatment of a variety of tumors and inflammatory diseases, affects normal tissues that have a high rate of proliferation, including the hematopoietic cells of the bone marrow and the gastrointestinal mucosal cells. To elucidate the role of free radicals and leukocytes in MTX-induced oxidative organ damage and the putative protective effect of L-carnitine (L-Car), Wistar albino rats were administered a single dose of MTX (20 mg/kg) followed by either saline or L-Car (500 mg/kg) for 5 days. After decapitation of the rats, trunk blood was obtained, and the ileum, liver, and kidney were removed for histological examination and for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen content. Our results showed that MTX administration increased the MDA and MPO activities and collagen content and decreased GSH levels in all tissues, while these alterations were reversed in L-Car-treated group. The elevated serum TNF-alpha level observed following MTX treatment was depressed with L-Car. The oxidative burst of neutrophils stimulated by Annexin V was reduced in the saline-treated MTX group, while L-Car abolished this inhibition. Similarly, flow cytometric measurements revealed that leukocyte apoptosis was increased in MTX-treated animals, while L-Car reversed these effects. Severe degeneration of the intestinal mucosa, liver parenchyma, and glomerular and tubular epithelium observed in the saline-treated MTX group was improved by L-Car treatment. These results suggest that L-Car, possibly via its free radical scavenging and antioxidant properties, ameliorates MTX-induced oxidative organ injury and inhibits leukocyte apoptosis. Thus, supplementation with L-Carnitine as an adjuvant therapy may be promising in alleviating the systemic side-effects of chemotherapeutics.

Animals↗
PubMed2006

The activities of antioxidant enzymes and the level of malondialdehyde in cerebellum of rats subjected to methotrexate: protective effect of caffeic acid phenethyl ester.

Methotrexate (MTX), a folic acid antagonist, is widely used as a cytotoxic chemotherapeutic agent. MTX-associated neurotoxicity is an important clinical problem. The aim of this study was to investigate the role of caffeic acid phenethyl ester (CAPE) on cerebellar oxidative stress induced by MTX in rats. A total of 19 adult male rats were divided into three experimental groups as follows: MTX group (MTX treated), MTX+CAPE group (MTX+CAPE treated), and control group. MTX was administered intraperitoneally (i.p.) with a single dose of 20 mg kg(-1) on the second day of experiment. CAPE was administered i.p. with a dose of 10 micromol kg(-1) day(-1) for 7 days. Malondialdehyde (MDA) levels and activities of superoxide dismutase (SOD) and catalase (CAT) were determined in cerebellar tissue of rats. MTX caused to significant increase in MDA levels (an important marker of lipid peroxidation) in the MTX group compared with the controls (p = 0.006). CAPE significantly reduced the MTX induced lipid peroxidation in the MTX+CAPE group compared to the MTX (p = 0.007). The activities of SOD and CAT were significantly increased in the MTX group when compared with the control group (p = 0.0001, p = 0.004, respectively). The increased activities of these enzymes were significantly reduced by CAPE treatment (p = 0.004, p = 0.034, respectively). As a result, CAPE may protect from oxidative damage caused by MTX treatment in rat cerebellum.

Animals↗
PubMed1989

Methotrexate-induced erythema multiforme.

The folic acid antagonist, methotrexate, has many applications in the treatment of neoplastic disease. While methotrexate produces several well-recognized toxic effects, cutaneous reactions are rare. A patient who developed classical erythema multiforme while receiving low-dose methotrexate as treatment of nonmetastatic gestational trophoblastic neoplasia is presented. Erythema multiforme has been associated with a variety of pharmacologic agents. It typically presents as a pruritic papular dermatitis of the extensor surfaces of the extremities and may require multiple skin biopsies to establish the diagnosis. Spontaneous reversal usually occurs with discontinuation of therapy. Patients developing erythema multiforme related to antineoplastic agents should be switched to an alternate regimen.

Adult↗
PubMed1981

Cytogenetic studies in patients treated with trimethoprim-sulfamethoxazole.

Cytogenetic studies were performed on bone-marrow cells from 12 patients with urinary tract infections treated with trimethoprim-sulfamethoxazole (T + S). An increased number of micronuclei was presented in the patients compared with the control group, whereas structural chromosomal aberrations were not seen. The present study shows that T + S, like other folic acid antagonists, damage the human genetic material, and confirms that the micronucleus test is more sensitive than chromosome analysis in detecting a cytogenetic effect of chemical agents in man.

Bone Marrow Cells↗
PubMed1983

Methotrexate-induced necrolysis.

A 72-year-old woman with a long history of recalcitrant psoriasis developed severe generalized erosions after receiving low-dose (7.5 mg) methotrexate. Her clinical picture was consistent with toxic epidermal necrolysis and showed a gradual response to systemic steroids and topical therapy. Patients with underlying dermatoses or previous cutaneous insults may be particularly prone to adverse cutaneous reactions resulting from folic acid antagonists.

Aged↗