Studies on the biological interrelationships of folic acid, citrovorum factor, and the antimetabolite, aminopterin.
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Aminopterin↗
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[A case of leukemia in a child treated with aminopterin, and a case of leukemic reaction in the course of infection].
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Aminopterin↗
[Aminopterin therapy of acute leukemias].
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Acute Disease↗
[Effect of methotrexate on the immune response in selected experimental models].
Methotrexate (MTX) is one of the immunosuppressory compounds applied in the prophylaxis and treatment of several diseases, including: rheumatoid arthritis, systemic lupus erythematosus, psoriasis, graft-versus-host disease and, in combination with other drugs, neoplastic diseases. Studies in humans and in animal model, of clinical disease, have demonstrated that MTX diminishes the clinical symptoms of various immunological disorders. MTX, an antagonist of folic acid synthesis, causes apoptosis in activated cells, primarily in the G1 and S phases of the cell cycle. One of its actions, is inhibition of the synthesis or activity of several proinflammatory cytokines. At high doses, MTX is cytotoxic to hemopoietic cells; low doses, however, promote hemopoiesis. MTX also induces the differentiation of monocytic tumor cells, which may explain, in part, its therapeutic effects in the treatment of some disorders. The compound suppresses both cellular and humoral immune response and mitogen-induced lymphocyte proliferation. These effects are dose- and time-dependent. The strongest suppressory activity is exerted when MTX is applied 24 or 48 hours after immunization or mitogen stimulation. Administration of MTX in unfavorable conditions such as stress or other diseases, diminishes its tolerance and increases its toxicity. Side-effects of MTX may be ameliorated by application of pharmacological synthetic agents and plant extracts. In summary, MTX has been an effective agent in suppressing immunological disorders (for 50 years) and is still finding many applications.
Animals↗
N-acetylcysteine ameliorates methotrexate-induced oxidative liver damage in rats.
BACKGROUND: Methotrexate (MTX), a folic acid antagonist, is widely used as a cytotoxic chemotherapeutic agent for malignancies as well as in the treatment of various inflammatory diseases. The efficacy of this agent is often limited by severe side effects and toxic conditions. The present study was undertaken to determine whether N-acetylcysteine (NAC), as a potent antioxidant compound, could ameliorate MTX-induced oxidative liver damage. MATERIAL/METHODS: A single dose of MTX (20 mg/kg, intraperitoneal) to rats was followed by intraperitoneal saline or NAC administration (150 mg/kg, MTX + NAC group) for the next 5 days. On the fifth day the rats were sacrificed and liver tissue samples were obtained and stored to measure reduced glutathione (GSH) and malondialdehyde (MDA) levels and myeloperoxidase (MPO), superoxide dismutase (SOD), and catalase (CAT) activity. RESULTS: MTX caused decreased GSH level and SOD and CAT activity and increased MDA level and MPO activity in the liver homogenates. These changes were significantly reversed by NAC treatment. CONCLUSIONS: These results confirm that administration of NAC decreases MTX-induced oxidative damage to the liver. These data indicate that NAC may be of therapeutic use in preventing hepatotoxicity in patients receiving MTX treatment.
Acetylcysteine↗
[Pneumocystis carinii pneumonia in patients with a severe combined immunodeficiency].
We describe three patients with Pneumocystis carinii pneumonia as the initial presentation of severe combined immunodeficiency disease. The pneumonia in the first patient was treated successfully with trimethoprim/sulphamethoxazole (Tmp/Smz). The second patient died despite therapy with Tmp/Smz and pentamidine. The third patient failed to respond to therapy with Tmp/Smz and pentamidine. He was subsequently treated with trimetrexate and leucovorin. Treatment with the new folic acid antagonist trimetrexate resulted in complete recovery. The case histories of these children serve to illustrate the clinical symptoms and new therapeutic modalities of P. carinii pneumonia in patients with immunodeficiency disease.
Humans↗
Intracranial calcification in dihydropteridine reductase deficiency.
We described the clinical status and computerized tomographic findings of two patients with tetrahydrobiopterin (BH4) deficiency due to impaired BH4 regeneration. In addition to an unfavorable course, cranial computerized tomography scans demonstrated severe cortical and subcortical atrophy and bilateral corticomedullary and basal ganglia calcifications in these two cases. The occurrence of calcification in the same distribution following the use of methotrexate, a folic acid antagonist, supported the hypothesis that there is a link between the metabolism of pterins and folate.
Brain↗
Migration of natural suppressor cells from bone marrow to peritoneal cavity by live BCG.
Delayed-type hypersensitivity (DTH) responses were suppressed in mice inoculated with bone marrow cells from mice that had been injected with 10(8) colony-forming units (CFU) of live BCG. Upon analysis of this DTH-suppression by the use of a macrophage migration inhibition (MI) assay, the in vitro correlate of DTH, suppressor macrophages in the peritoneal cavity were found to play an important role in DTH suppression. However, neither suppression of DTH nor production of suppressor macrophages was observed in mice inoculated with bone marrow cells from mice that had been injected with methotrexate (MTX), a folic acid antagonist, and 10(8) CFU of live BCG. Moreover, suppressor cells against the MI activity of peritoneal exudate cells from BCG cell wall-immunized mice existed in bone marrow cells from normal mice, natural suppressor (NS) cells, and they were sensitive to MTX. In addition, these NS cells phagocytized carbonyl iron particles, were adherent to Sephadex G-10, and had Fc receptors, but they had no B or T cell markers, suggesting that these cells belonged to a macrophage compartment. From this evidence, we hypothesized that the origin of suppressor macrophages in the peritoneal cavity induced by live BCG injection was MTX-sensitive NS cells in bone marrow, and that these NS cells were stimulated by a small dose of live BCG trapped in bone marrow after i.v. injection of a high dose of live BCG and migrated from bone marrow to the peritoneal cavity.
Animals↗
[Methotrexate and its drug resistance].
Methotrexate (MTX), a folic acid antagonist, is among the most active known drugs for clinical cancer therapy. The mechanisms of resistance to MTX have been extensively studied, and several mechanisms have been reported so far. Those are decreased cell permeability, increased synthesis of dihydrofolate reductase (DHFR), which is the target enzyme of MTX, decreased polyglutamation of MTX, and decreased binding capacity of MTX to DHFR. Recent basic studies revealed that an increase of DHFR synthesis is the result of a proportional amplification of DHFR gene, and that polyglutamation of MTX plays an important role in its action. High-dose methotrexate (HDMTX) therapy has a good rationale for overcoming MTX resistance. However, many clinical trials of HDMTX during past decade have not demonstrated any apparent clinical efficacy except childhood ALL and ostosarcoma. Further research would be necessary for the improvement of the therapy using MTX.
Acute Disease↗
Acanthosis nigricans-like hyperpigmentation secondary to triazinate therapy.
Cutaneous hyperpigmentation resembling acanthosis nigricans developed in two patients with malignant brain tumors following chemotherapy with triazinate (Baker's Antifol), a folic acid antagonist. In both cases, the eruption resolved after the cessation of drug administration and reappeared after the reinstitution of triazinate therapy. A skin biopsy specimen from one patient showed microscopic changes consistent with those found in acanthosis nigricans. The other patient had a decreased serum folate level that returned to normal as the hyperpigmentation resolved. Folate may have a role in triazinate-induced acanthosislike hyperpigmentation.
Acanthosis Nigricans↗
Introduction of antifolics in psoriasis. A twenty-five year retrospect of antineoplastic agents in nonmalignant disease.
Presented herein is a review of the beneficial use of the folic acid antagonist, aminopterin, in the treatment of psoriasis and other dermatologic disorders.
Adult↗
[Determination of relative values of de novo biosynthesis and salvage pathway of thymidylate formation in rat decidual tissue].
A method for the determination of relative values (%) of two pathways of thymidine-5'-phosphate (dTMP) formation, e.g. via de novo biosynthesis and through thymidine reutilization (salvage pathway), is proposed. It is shown that the relative values of dTMP formation through the salvage pathway in the mesometrial part of developing decidua in pregnant rats (9-11th day of ppregnancy) are 1.5-3.4 times higher as compared to those in the antimesometrial part. When dTMP biosynthesis is suppressed by aminopterine, up to 80% of total DNA thymind is synthesized at the expense of thymidine reutilization. The incorporation of 3H-thymidine into DNA was thereby increased approximately 8-fold irrespective of the decrease in the DNA synthesis rate (approximately 2.4 times). The dependence of the relative values of the thymidine reutilization pathway on the correlation of the thymidylate synthetase and thymidine kinase activities in the tissue is discussed. The ability of the cells to reutilize thymidine is interpreted in terms of their relative resistance to the effect of folic acid antagonists.
Animals↗
Effect of "aminopterin" on epithelial tissues.
The folic acid antagonist, 4-aminopteroyl glutamic acid ("aminopterin"), is a potent inhibitor of growth and of connective tissue proliferation. The present study indicates that the suppressive effects of "aminopterin" on epithelial structures are more striking than on connective tissue, as revealed by observation of interference with wound healing and epithelization, atrophy and ulceration of mucosa, alopecia, and prompt suppressive effects in such dermatologic disorders as psoriasis and chronic indurative dermatoses. "Aminopterin" was administered orally in daily doses of 1.5 to 2.0 mg. to thirteen patients with psoriasis (of whom six had associated arthritis) and to five patients with chronic indurative dermatoses. The latter included one patient with chronic atopic eczematoid dermatitis with associated asthma, one with chronic eczematoid seborrheic dermatitis, one with chronic discoid lupus erythematosus involving the face, and two with scleroderma. In all patients there were remissions in cutaneous lesions, which appeared most commonly between the 5th and 10th day of "aminopterin" therapy. Treatment was interrupted in most patients after an initial course of 14 to 28 mg. because of the regular occurrence of shallow ulceration of the buccal mucosa and frequent development of abdominal cramps. Remissions persisted for periods ranging from two weeks to several months, after which lesions returned which responded to further courses of "aminopterin." The therapeutic response was more complete in the seven patients with psoriatic arthritis than in in six subjects with uncomplicated psoriasis. In four patients with psoriatic arthritis in whom the responses to "aminopterin" and cortisone were compared, arthritic manifestations were considerably more relieved by cortisone, but improvement in psoriasis was consistently more complete and more sustained with "aminopterin." No evidence of a summative effect of cortisone and "aminopterin" on psoriasis was observed when the two were employed concomitantly, although amelioration of arthritic symptoms was more complete than when cortisone was given alone. Topical application of "aminopterin" in a 1% ointment was found to be ineffective. "Aminopterin" is a toxic drug, and its administration must be carefully supervised. The citrovorum factor has proved useful in overcoming "aminopterin" toxicity but interferes with its therapeutic effects. It is suggested that "aminopterin" may prove useful in other dermatologic disorders and in cutaneous manifestations of some systemic diseases which, in certain instances, have been temporarily benefited by cortisone.
Adult↗
[Investigation on the influence of trimethoprim at the intrauterine development in the rat (author's transl)].
The present investigations was made to check the effects of repeated oral applications of the chemotherapeutic effective pirimidinsubstance trimethoprim (pure substance) at the intrauterine development in the wistar rat. The agent was given with a throat tube suspended in hydroxyacetylcellulose from the 5th to the 7th, from the 8th to the 10th and from the 11th to the 13th day p. c. The dosage was 1,500, 1,000, 750 and 200 mg trimethoprim per kg bodyweight. The valuation of the fetal development was made after the subsequent parameters: mean implantationrate, resorptionrate, mean fetal bodyweight. Statement of anomalies by inspection of the body surface shape and the brightened skeleton. The dosage of 200 mg TMP/kg bodyweight influences the fetal development only a little. Doses of 1,500, 1,000, and 750 mg TMP/kg bodyweight however show a high toxicity for the used rat strain as well for the mother animals as for the fetuses of the surviving animals. The observed increased resorption rates diminishing of the average fetal bodyweight, anomalies of the body shape and different anomalies of the skeleton are typical effects of folic acid antagonists.
Abnormalities, Drug-Induced↗
[Methotrexate treatment of patients with prednisolone dependent bronchial asthma].
In this review we went through eight placebo-controlled clinical trials of the folic acid antagonist methotrexate in the treatment of bronchial asthma. The studies, which differ in their methods and findings, are reviewed critically. Some studies seem to give documentation of methotrexate as an effective drug in reducing the corticosteroid requirements in patients with chronic corticosteroid-dependent asthma. Adverse effects are wellknown from the use of methotrexate in patients with rheumatoid arthritis and include nausea, diarrhoea, vomiting, transient increases in liver enzymes, alopecia and stomatitis. Rare but potentially life-threatening adverse effects are interstitial pneumonitis, opportunistic infections, bone marrow- and renal insufficiency. The role of methotrexate in patients with chronic corticosteroid-dependent asthma still needs to be clarified. Practical guide-lines in treating asthma patients with methotrexate are suggested.
Asthma↗
Methotrexate for the treatment of chronic corticosteroid-dependent asthma.
The role and adverse effects of methotrexate in the treatment of chronic corticosteroid-dependent asthma are discussed. Methotrexate is a folic acid antagonist that has been used as an anti-inflammatory agent in the treatment of arthritis. It also appears to be effective in reducing the corticosteroid requirements in patients with chronic corticosteroid-dependent asthma, a use that was first reported in 1986. Studies of this use of methotrexate in adults support a trial of methotrexate in patients with severe asthma who have been unable to discontinue corticosteroid use despite aggressive management of their asthma and who are experiencing severe corticosteroid toxicity. Experience with methotrexate in children with asthma is limited to case series. Adverse effects associated with the use of methotrexate for treatment of corticosteroid-dependent asthma include nausea, elevated serum aminotransferase, diarrhea, and thinning of hair. While methotrexate appears to reduce corticosteroid requirements in patients with chronic corticosteroid-dependent asthma, its role in asthma therapy still needs to be clarified.
Adrenal Cortex Hormones↗
[Investigations on the effect of the combination sulfamoxole/trimethoprim on fertility and fetal development in rats and rabbits (author's tranls)].
The chemotherapeutically active combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) in a dose ratio of 5:1 (CN 3123, Nevin, Supristol) was investigated, with respect to teratogenicity, effects on fertility and reproduction and influence on peri- and post-natal development. Experiments with the combination and partly with the single substances were done on Sprague-Dawly and Wistar rats and on rabbits (New Zealand White). With regard to the known effects of trimethoprim in this field--fetal malformations typical of those caused by folic acid antagonists--it was to clarify whether or not potentiation phenomena or new toxic effects occur with the combination. The results were as follows: 1. CN 3123 is teratogenically and fetotoxically active when given in very high doses to pregnant rats and rabbits during the critical phase of organogenesis (day 8-15 of pregnancy in rats, day 8-14 in rabbits). There were malformations, decrease in the number of pups and an increase in the number of absorption sites. Litter size and litter weight were reduced. The malformations observed were cleft palates, rarely cleft lips, micrognathies and shortening of limbs. Doses up to 180 mg/kg CN 3123, corresponding to more than tenfold the daily maintenance dose in man, were without any effects on all parameters observed. Toxic effects were observed in Sprague-Dawley rats at a dose level of 420 mg/kg and in Wistar rats with 600 mg/kg, corresponding to the effects seen following 100 mg/kg of trimethoprim alone. Sulfamoxole in the corresponding dose of 500 mg/kg caused no embryotoxic effects in the rat. In rabbits 600 mg/kg CN 3123 induced no malformations but increased fetal loss. Therefore it can be concluded, that the teratogenic and fetotoxic effects seen with high doses of CN 3123 are due to the amount of trimethoprim in the combination. The observed effects with the combination are quantitatively related to those seen with trimethoprim. 2. CN 3123 in high doses which are teratogenic also provoked a reduction of growth of the animals. Food consumption and weight gain were reduced in dams with 420 and 600 mg/kg CN 3123. In this dose range the pup weights and the weight gain of the offspring of dams with continued dosing during lactation were also reduced. Variation rate including retardations was increased. The depressing effect of CN 3123 in high doses on food consumption and weight gain is known from long-term toxicological studies previously described [7]. 3. CN 3123 even with high doses has no effects on the fertility of male and female rats. The number of corpora lutea and implantations and also the pregnancy rate were unaffected when either the female or the male rats used for mating had been treated. There was also no influence on mating activity of the male animals treated. 4. According to the results of the fertility study with treatment of the male rats for a period of ten weeks or more there were no signs of mutagenic effects due to CN 3123.
Abnormalities, Drug-Induced↗
Induction of sister chromatid exchanges by pyrimethamine in human lymphocyte cultures.
This study examined the effect of pyrimethamine (PYR) on sister chromatid exchanges (SCEs) in human lymphocytes. PYR is a folic acid antagonist used for the treatment of malaria and toxoplasmosis. PYR was added to peripheral blood lymphocyte cultures at three different doses: 0.05, 0.1, and 0.2 mg/ml. The results of the cytogenetic and statistical evaluations showed that the frequency of SCEs increased significantly in a dose-dependent manner. Thus, it is shown that PYR has a genotoxic effect on human chromosomes.
Adult↗