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Methotrexate (MTX) is still the gold standard in the treatment of rheumatoid arthritis and is used worldwide in more than 0.5 million patients with RA. Much hope is currently associated with the individualization of therapy provided to RA patients. The search is underway for biochemical and clinical markers that would be useful in predicting good response to MTX therapy. Along with clinical factors, genetic predisposition may also be helpful. Polymorphism of genes participating in MTX metabolism may affect the drug’s efficacy and the rate of adverse effects. Pharmacogenetic studies may contribute to more effective individualization of therapy for RA patients. There are many potential enzymes and transport proteins present in polymorphic forms, which are involved in transport of MTX into the cell, its metabolism and elimination from the cell. There is a chance that in the future through individualized therapy we will be able to customize therapy (type of drug, dose, route of administration) to the molecular subtype of the disease and the genotype of the patient. Patients with a specific type of polymorphism would require more frequent monitoring of the efficacy and safety of treatment. Note, however, that genetic predisposition is only one of the factors contributing to differences in pharmacotherapy in individual patients.

Much hope is currently associated with individualization of therapy provided to rheumatoid arthritis (RA) patients. The search is underway for biochemical and clinical markers that would be useful in prediction of a good response to methotrexate (MTX) therapy. Along with clinical factors, genetic predisposition may also be helpful. Polymorphism of genes participating in MTX metabolism may affect the drug’s efficacy and the rate of adverse effects. Pharmacogenetic studies may contribute to more effective individualization of therapy for RA patients. The purpose of the study was to determine the significance of gene polymorphisms MTHFR C677T and A1298C for efficacy of MTX therapy in RA patients. Patients possessing determined polymorphisms should be particularly carefully evaluated because of a higher risk of occurrence of adverse effects.

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.

Interleukin-1 (IL-1) is one of the main inflammatory mediators associated with development of rheumatoid arthritis (RA). Deficiency in secretion of the natural IL-1 antagonist was found in RA patients, and enhanced joint inflammation. This finding was confirmed by numerous studies using the animal model of the disease. Two randomized, multicenter clinical trials with anakinra, a recombinant IL-1 receptor antagonist (rHHHuIL-1Ra), revealed that application of anakinra with or without methotrexate induces remission (ACR 20) in 38-71% of patients with RA. Induction of remission was dose and treatment-time-dependent. The present paper reviews theoretical application of rHuIL-1Ra in patients with RA and summarizes results of published clinical trials of the drug.

The paper present modern views on turnover, mechanism of action and application of methotrexate. Contraindications and the most frequent side effects observed in certain number of patients treated with this drug are discussed.

The first crucial step of cell recruitment to the sites of inflammation is adhesion and motility, which are interdependent phenomena. The purpose of our study was investigate the influence used anti-inflammatory drugs (Aspirin, Cyclosporin A, Methotrexate) and endogenous substances of anti-inflammatory activity (Cortisol, TGF-beta) on these phenomena. Lymphocytes from healthy subjects were preincubated with various concentrations of these substances and adhesion to plastic bound CD11a/CD18, CD11c/CD18, CD44 and CD62L mAbs was determined. Simultaneously, cell motility was investigated after Boyden method. We found significant reduction of cell adhesion to all the ligands used. Furthermore we observed significant dose dependent increase in motility of these cells. These data indicate that simultaneous enhancement of motility and reduction of adhesion might be a common pathway for the mechanisms of action of anti-inflammatory agents.

The aim of the experimental studies, carried-out on 32 rabbits, was to explain the hypotensive effect of cytostatic drugs. It was found that a statistically significant lowering of the intraocular pressure without any changes in the coefficient of the outflow of intraocular fluid occurred on the 1st, 2nd, 3rd and 4th day after administration of cytostatic drugs. On the 2nd and 3rd day, there were also observed a decrease of sodium and an increase of potassium blood concentrations. It ought to be supposed that those changes caused disturbances in Na/K ATP-ase activity with an inhibition of the active transport in the ciliary epithelium and a decrease of the secretion of intraocular fluid in ciliary body.

The effect of benzylpenicillin and doxycycline on toxicity and anticancer activity of cyclophosphamide and methotrexate in mice was studied. Benzylpenicillin applied both at once repeatedly enhances anticancer activity of cyclophosphamide against L 1210 leukemia within limited range of CP. Benzylpenicillin does not change anticancer activity of methotrexate, but doxycycline of both cyclophosphamide and methotrexate, against L 1210 leukemia in mice.

In 10 children after operations for cerebellar medulloblastoma treated with intrathecal injections of methotrexate changes were studied in the concentration of total protein in the cerebrospinal fluid and in different electrophoretic fractions of proteins. The investigations were begun 1 to 3 months after the operation and were continued usually at monthly time intervals. In each child considerable variations were observed in the concentration of total protein as well as in the proportions of protein electrophoretic fractions in the period of treatment lasting from 14 to 59 months after the operation. Significant individual variations were observed also in the level of total protein fractions pattern in the cerebrospinal fluid. Out of 116 electrophorograms in 42 the protein fraction pattern in the cerebrospinal fluid approached very much that found in patients with cerebellar medulloblastoma before the operation, with a significant rise in the proportion of albumins. The origin of cerebrospinal fluid proteins is discussed.