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Various studies have shown the effectiveness of the drug cyclosporin A in treating active rheumatoid arthritis, a joint disease characterized by inflammation, stiffness, and swelling of the joints; overgrowth of cartilage tissue; and pain. A frequent side effect of cyclosporin A treatment is nephrotoxicity, or adverse effects on the kidney. The mechanism underlying cyclosporin A-induced nephrotoxicity is not known, but may involve changes in the kidney metabolism of eicosanoids, metabolites of arachidonic acid. Eicosanoids include prostaglandins, thromboxane, and leukotrienes, which are natural factors involved in the regulation of various cell processes. The effects of cyclosporin A on the excretion of eicosanoids by the kidneys were assessed in RA patients who were not being treated with nonsteroidal anti-inflammatory drugs. The blood levels of creatinine, a nonprotein blood factor that increases in advanced kidney disease, were 32 percent above the levels measured at the start of the study. Blood flow through the kidney had decreased by 21 percent, and the glomerular filtration rate, an index of the speed at which blood is processed by the kidney, was decreased by 16 percent. Cyclosporin A treatment was associated with an increase in only one type of eicosanoid, namely 2,3-dinor thromboxane B2. These findings show that cyclosporin A treatment is associated with a specific increase in thromboxane B2 metabolite, which is correlated with decreased blood flow through the kidney. (Consumer Summary produced by Reliance Medical Information, Inc.)

The human neutrophil peptide-generating protease, which generates a low molecular weight vasoactive peptide from a plasma protein substrate, is directly fibrinolytic and cleaves human fibrinogen in a manner distinct from plasmin. Fibrinogen was reduced from 340,000 Mr to derivatives of 270,000-325,000 Mr during interaction with the protease at enzyme-to-substrate ratios of 0.3 or 1.0 microgram/1.0 mg. The 310,000-325,000 Mr cleavage fragments exhibited prolonged thrombin-induced clotting activity but were able to be coagulated, whereas the 270,000-290,000 Mr fragments were not able to be coagulated. Anticoagulants were not generated at either enzyme dose. As analyzed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis in 4-30% gradient gels and 10% gels stained for protein and carbohydrate, the diminution to 310,000-325,000 Mr and the prolongation of thrombin-induced clotting time resulted from cleavage of the fibrinogen A alpha chain. The further decrease in size to 270,000-290,000 Mr was associated with B beta-chain and gamma-chain cleavage and an inability to form gamma-gamma dimers. The neutral peptide-generating protease, a distinct human neutrophil neutral protease with fibrinolytic and fibrinogenolytic activities comparable to those of plasmin on a weight basis, cleaves fibrinogen in a manner that is distinct from the action of plasmin, leukocyte elastase, and leukocyte granule extracts. It may be that the concerted action of this neutrophil protease to generate a vasoactive peptide and to digest fibrinogen and fibrin facilitates neutrophil movement through vascular and extravascular sites.