Leflunomide has been shown to be very effective in preventing and curing several autoimmune animal diseases. Further, this agent is as effective as cyclosporin A in preventing the rejection of skin and kidney transplants in rats. Preliminary results from patients suffering from severe cases of rheumatoid arthritis demonstrated that clinical and immunological parameters could be improved with leflunomide therapy. Mode of action studies revealed that this substance antagonizes the proliferation inducing activity of several cytokines and is cytostatic for certain cell types. In this light, we could show that tyrosine phosphorylation of the RR-SRC peptide substrate and the autophosphorylation of the epidermal growth factor (EGF) receptor were, dose dependently, inhibited by leflunomide. EGF activates the intrinsic tyrosine kinase of its receptor, which stimulates the phosphorylation of a variety of peptides, the amino acid residue in all cases is tyrosine. These results indicate that much of leflunomide's activity could be due to the inhibition of tyrosine-kinase(s), which is an important general mechanism for the proliferation of various cell types. Thus, leflunomide, which is effective against autoimmune diseases and reactions leading to graft rejection, would seem to have a mode of action separating it from known immunosuppressive drugs.
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. Maximum values were reached at the 23rd day with an acid secretion 4 times higher than in healthy animals. The enhanced hydrochloric acid secretion in adjuvant arthritic rats was confirmed with the aid of the gastric perfusion technique according to Ghosh and Schild and by the finding that the gastric contents of conscious arthritic rats under standard feeding conditions showed a statistically significant higher acidity (pH 2.5) than normal rats (pH 4.0). Adjuvant arthritic rats with acute bile fistulas exhibited a basal and stimulated bile and pancreatic secretion like normal rats. The gastric mucosa of rats with adjuvant disease is highly sensitive to the irritant effect of gastric hypersecretion in the pylorus-ligation technique. The ulcer rate increases during the progress of the disease with a maximum of 70% at the 37th day. Normal rats with 4 h-pylorus ligation showed no macroscopically visible lesions. Increased sensitivity of the gastric mucosa against the ulcerogenic activity of non-steroidal anti-rheumatic drugs was demonstrated for aspirin and indomethacin. The etiological role of disease stress for the high susceptibility of the arthritic rat to gastric ulceration is discussed.
The present studies on duct ligated dogs and rabbits are an attempt to demonstrate functional alterations in glucose metabolism: 1. In rabbits the insulin reserve in the pancreatic gland was reduced to about one fifth of its normal value. 2. In dogs, as well as in rabbits, the values of fasting blood glucose remained norreal for a period of 12 months following the operation. In rabbits the intragastric, but in dogs both the intragastric and the intravenous glucose tolerance were impaired. 3.In duct ligated dogs, the increase in serum IRI was diminished after intragastric and i.v. glucose load, as well as after injection of glucagon. Attempts are being made to adapt the model for special studies concerning the early state of diabetes.
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