Restriction of de novo pyrimidine biosynthesis inhibits Th1 cell activation and promotes Th2 cell differentiation.

Leflunomide, an inhibitor of de novo pyrimidine biosynthesis, has recently been introduced as a treatment for rheumatoid arthritis in an attempt to ameliorate inflammation by inhibiting lymphocyte activation. Although the immunosuppressive ability of leflunomide has been well described in several experimental animal models, the precise effects of a limited pyrimidine supply on T cell differentiation and effector functions have not been elucidated. We investigated the impact of restricted pyrimidine biosynthesis on the activation and differentiation of CD4 T cells in vivo and in vitro.

Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases.

Leflunomide (Arava) has recently been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). The drug, due to its protective effects on structural joint damage, has been classified as a disease modifying anti-rheumatic drug (DMARD). Leflunomide is structurally dissimilar from other drugs currently used to treat RA and exhibits a different mechanism of action.

Effects of tiaprofenic acid on urinary pyridinium crosslinks in adjuvant arthritic rats: comparison with doxycycline.

Objective And Design: To study the effects of tiaprofenic acid and doxycycline on urinary pyridinium crosslinks and paw swelling in adjuvant arthritic rats, and to gain additional information on the drugs' inhibitory potential vs. in vitro targets, such as enzyme activity of matrix metalloproteinases and cytokine generation.

Material: 124 male Wistar Lewis rats; for the in vitro studies human matrix metalloproteinases and human mononuclear cells were used.

Complexity of IL-1 beta induced gene expression pattern in human articular chondrocytes.

The mRNA fingerprinting technique, differential display reverse transcription polymerase chain (DDRT-PCR), was used to detect changes in the overall pattern of gene expression in human articular knee chondrocytes-induced by interleukin-1 beta (IL-1 beta), the prototypical inducer of catabolic responses in degenerate joint diseases. One hundred different primer combinations generated approximately 10,000 different PCR fragments for IL-1 beta treated, as well as for untreated human chondrocytes, cultivated in alginate beads. This represented 53% of all expressed chondrocyte genes as based on statistical considerations.

Inhibitory effects of pentoxifylline on LPS-induced leukocyte adhesion and macromolecular extravasation in the microcirculation.

Pentoxifylline (PTX) has been shown to combat effectively endotoxin induced symptoms of shock or inflammation by reducing both leukocyte activation and endogenous cytokine formation. With regard to blood perfusion, inflammation is defined as a local reaction to injury of the living microvasculature and its content. Leukocyte margination, rolling, adhesion, and emigration is mediated by adhesion molecules along the endothelium of postcapillary venules and is considered to be an important step in the inflammatory response.

Effects of leflunomide on the course of listeriosis in mice. Short communication.

The intensity of an infection with Listeria monocytogenes depends on the immunological stab1p4f the body. Impairment of the specific or unspecific defence can lead to severe and partly fatal complications such as meningitis or septicaemia. In a normal defence situation affected individuals are often not diagnosed because the infection appears as an unspecific indisposition.

Chondrocytes and antirheumatic drugs.

Effects of antirheumatic drugs upon cartilage matrix metabolism have been studied in a variety of chondrocyte in vitro systems. When compared longterm in 60 experiments under standardized conditions, articular chondrocytes cultured in agarose exhibit variability in proteoglycan synthesis, and its suppression by interleukin 1 (IL-1), but a high reproducibility in the modulation of these effects by antirheumatic drugs. Pentosan polysulfate, tenidap, tiaprofenic acid, and RO 31-9790 all compensated to a certain extent the IL-1 induced suppression of matrix synthesis in bovine chondrocytes, but only for tiaprofenic acid could this be confirmed using chondrocytes of human origin.

Immunomodulation of proteoglycan-induced progressive polyarthritis by leflunomide.

Proteoglycan-induced arthritis is a mouse model displaying many similarities to human rheumatoid arthritis and ankylosing spondylitis which has been documented by clinical and histopathological studies. The development of the disease in genetically susceptible BALB/c mice is dependent upon the expression of both cell-mediated and humoral immunity to host mouse cartilage proteoglycan. Since both development and regression of acute inflammatory processes in joints correlate directly with the serum antibody level to mouse cartilage proteoglycan, it is believed that these autoreactive antibodies may play a key role in the pathological mechanism of proteoglycan-induced arthritis.

Immunosuppressive activity of 15-deoxyspergualin (15-DOS) on various models of rheumatoid arthritis.

Based on the promising results obtained thus far in various auto-immune disease models, the authors have further elucidated the disease-modifying potential of the new immunosuppressive drug 15-deoxyspergualin (15-DOS) in models of inflammatory and chronic degenerative joint disease of adjuvant arthritis (AA) and collagen type-II induced arthritis (CIA) in Lewis rats and spontaneously developing polyarthritis in MRL/1 mice. Treatment of AA animals with 15-DOS starting with the day of adjuvant injection prevented the disorder from spreading to the non-injected extremity. The drug also reduced the arthritis index (47% inhibition).

Leflunomide (HWA 486) inhibits experimental autoimmune tubulointerstitial nephritis in rats.

Experimental tubulointerstitial nephritis (TIN), induced in Brown Norway rats, is an autoimmune disorder in which afflicted animals display high levels of serum autoantibodies directed against antigens present on the tubular basement membrane (TBM). Serious functional damage, due to lesions of the kidney cortex, is evident 10 days after disease initiation. In an earlier study, we could show that cyclosporin A (CsA), an immunosuppressive drug, effectively prevented the onset of this illness, although it did not inhibit the formation of TBM autoantibodies.

Substituted 3-phenyl-7H-thiazolo(3,2-b)(1,2,4)triazin-7-ones as antiinflammatory agents with immunomodulating properties.

After structure-activity relationship studies (SAR) on a novel class of substituted thiazolo(3,2-b)(1,2,4)triazin-7-ones, HWA-131 (3-(3,5-di-tert.butyl-4-hydroxyphenyl)-7H-thiazolo(3,2-b)(1,2,4)triaz in-7-one) was selected for incremental pharmacological investigations. This compound was effective in not only preventing, but also curing established arthritic disorders of rats such as adjuvant and type II collagen arthritis as well as those of mice such as chronic graft-versus-host (CGVH) disease, a model for systemic lupus erythematosus (SLE).

Influence of the new angiotensin converting enzyme inhibitor ramipril on several models of acute inflammation and the adjuvant arthritis in the rat.

Paw oedema in the rat by carrageenin and kaolin partially caused by Hageman factor activation was potentiated by the new angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl-L-alanyl]-(lS,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid] (ramipril, Hoe 498) due to its inhibition of kininase II which results in increased bradykinin levels.

Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential antirheumatic activity--I. Disease modifying action on adjuvant arthritis of the rat.

The new isoxazol derivative, N-(4-Trifluoro-methylphenyl)-5-methylisoxazol-4-carboxamide (HWA 486) has been investigated as to its disease modifying activity on adjuvant arthritis of the Lewis rat. This compound was able to prevent the onset of the adjuvant disease, provided the therapy was started within the first 12 days after its induction, reflecting properties similar to that of immunosuppressive agents. If therapy started later than 12 days, the substance was still able to reduce the degree of inflammation and arrest its progress as long as it was administered, i.

Alterations in the gastro-intestinal functions during the development of adjuvant disease in rats.

Gastric biliary and pancreatic secretions were examined in Lewis rats with adjuvant-induced polyarthritis. By application of the pylorus-ligation technique according to Shay for 4 h, a marked increase in gastric secretion was detected from day 11 to day 54 after adjuvant injection. The changes were manifest by a decrease of pH and an increase of secretory volume as well as total acid output.

Gastrointestinal and cardiovascular effects of the prostaglandin analogue Hoe 260.

Hoe 260 is a long-lasting and potent antisecretory and cytoprotective prostaglandin E2-analogue, having a favourable split between therapeutic gastric effects, effect on blood pressure and intestinal side effects; this compound could be a promising drug in ulcer therapy. (formula; see text)

Studies on the effect of tolbutamide, glibenclamide, HB 699, and glucose on serum insulin and blood glucose in gastro-enterectomized dogs.

The influence of intravenously administered tolbutamide, glibenclamide, HB 699, and glucose on serum insulin and blood glucose kinetics was examined in 36 enterectomized dogs. The substances induced an immediate and long-lasting insulin release even in the absence of all insulinotropic intestinal mediators. Maximum and mean insulin concentrations after treatment, measured for 180 minutes, were markedly higher in resected dogs than in sham operated or non-operated animals.