Objective. To assess the safety and effectiveness of leflunomide versus placebo in patients with active rheumatoid arthritis (RA) treated for 6 months.Methods. Four hundred two patients were randomly assigned to receive placebo or leflunomide at 5 mg, 10 mg, or 25 mg daily. A washout period of 6-12 weeks from prior second-line therapy was required.Results. Statistically significant improvement in primary and secondary outcome measures, as well as by responder analyses, occurred in the 10-mg and 25-mg dosage groups compared to placebo. Twenty-one patients (7.0%) in the active treatment groups withdrew due to adverse events (AEs). The incidence of AEs was higher with leflunomide than with placebo. Gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia were more common in the
The substitution of recombinant human erythropoietin (rhEPO) in chronic hemodialysis patients is often associated with the development of severe hypertension. In the present study, a systematical echocardiographic analysis was performed in 25 patients on maintenance hemodialysis during rhEPO therapy for at least 4 months. Referred to the total group, indices of left ventricular size decreased significantly. Left ventricular total volume and left ventricular mass were reduced considerably. Fractional fiber shortening and ejection fraction showed an impressing improvement. At a constant heart rate, stroke volume and cardiac output were reduced. Myocardial thickness did not alter under chronic rhEPO therapy. When subgroups were formed with respect to changes in blood pressure, all parameters investigated behaved very similar to the total group, irrespective of changes in blood pressure. Five patients with coronary heart disease and clinical signs of myocardial insufficiency were evaluated separately. These patients showed a decrease in left ventricular size and no evidence of a deterioration of myocardial function. We conclude from our results that rhEPO therapy in patients on maintenance renal replacement therapy has beneficial effects on left ventricular size and function; these effects are not significantly counteracted by the development of hypertension.
Diseases accompanied by severe cardiac impairment like sepsis and chronic uremia are frequently linked to an increase in cytokine release. In order to investigate possible toxic effects of the immune mediators on myocardial cells, we studied the contractility of cardiac myocytes and the de novo formation of stress proteins in cultured heart cells under cytokine exposition. All cytokines investigated induce, concentration-dependently, arrhythmias and cessation of spontaneous contractions. Interleukin(IL)-2, IL-3, IL-6, and tumor necrosis factor (TNF) stimulate the synthesis of a 30 kD stress protein in heart cells, whereas IL-1 additionally evokes two proteins of the 70 kD family. These findings confirm a direct interference of the interleukins and TNF with myocytes and, especially, myocardial protein formation. As the induction of stress proteins makes cells more resistant towards a subsequent challenge, the cytokines are possibly involved in the activation of cell protecting mechanisms in cardiac myocytes.
Cardiovascular complications determine the prognosis of patients with chronic renal failure. The contribution of compounds retained during uremia to specific myocardial lesions is controversal. We investigated the contractility of spontaneously beating mouse cardiac myocytes in culture under perfusion with sera derived from patients on maintenance hemodialysis and test solutions containing possible toxins. Cellular contractility under defined environmental conditions is determined by a computer-assisted digital image analysis. ‘Uremic sera’, creatinine, urea, and combinations of these compounds reduce inotropy of the cultured heart cells, induce arrhythmias or asynchronies in a concentration-dependent manner. We propose the myocyte perfusion technique as an in vitro approach to identify cardiotoxins in the body fluids of chronically uremic patients.
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