Heat shock proteins (HSP) are a family of ubiquitous and phylogenically highly conserved proteins [1]. Autoreactivity to HSP is often associated with autoimmune pathology. Previous studies have demonstrated the presence of autoantibodies to the HSP90 in a significant proportion of patients with systemic lupus. Anti-HSP90 autoantibodies of the IgG class were detected in approximately 50% [2] and 26% [3] and of IgM class in 35% [3] of unselected patients with SLE. The presence of high titre anti-HSP90 autoantibodies was found to correlate with renal involvement and low C3 levels [3]. Although HSP90 is an intracytoplasmic protein, surface expression of HSP90 on peripheral blood mononuclear cells was found in approximately 25% of the patients with systemic lupus erythematosus (SLE) during active disease [4]. It has been shown that the increased expression of HSP90 is due to the enhanced transcription of the HSP90a gene [5]. Although these results indicate an association of anti-HSP90 autoreactivity with SLE, no direct involvement of HSP90 and anti-HSP90 antibodies in the pathogenesis of the disease has been proven. Moreover, normal human IgG (represented by pooled preparation for i.v. use -IVIg) has been found to contain considerable amounts of low-affinity anti-HSP90 natural autoantibodies [6].The aim of the present study was to investigate the role of HSP90 as an autoantigen in the renal injury in SLE by looking for HSP90 containing immune complexes in kidney biopsies of lupus patients. Since the most probable cause for such deposits is the presence of high titre anti-HSP90 autoantibodies in the sera of SLE patients and considering the fact that natural anti-HSP90 autoantibodies are found also in healthy individuals, we examined the possibility of using this autoreactivity as a model to study the relation between natural and disease-associated autoantibodies.
169Lupus-specific kidney deposits of HSP90 are associated with altered IgG idiotypic interactions of anti-HSP90 autoantibodies
SUMMARYPrevious studies have shown that autoantibodies to heat shock protein 90 (HSP90) are elevated in a significant proportion of patients with systemic lupus erythematosus (SLE) who are more likely to have renal disease and a low C3 level. Using samples from 24 patients, we searched for glomerular deposits of HSP90 in renal biopsy specimens from seven patients with lupus nephritis and 17 cases of glomerulonephritis from patients without SLE. Positive glomerular immunofluorescent staining for HSP90 was observed in six of seven cases of SLE and positive tubular staining in two of seven SLE patients. The staining for HSP90 was granular in nature and was located in subepithelial, subendothelial and mesangial areas. None of the non-SLE renal biopsies revealed positive staining for HSP90 deposition. Further we showed the presence of anti-HSP90 IgG autoantibodies in IgG from sera of patients with SLE as well as in normal human IgG (IVIg). In normal IgG this autoreactivity could be adsorbed almost completely on F(ab¢) 2 fragments from the...
Galanthamine hydrobromide (Nivalin®, dose 10 mg) was given subcutaneously and orally to 8 volunteers. Galanthamine and its metabolites were quantified in plasma and urine by reversed-phase HPLC. An unusual two-stage absorption and biexponential drug decline were observed. Galanthamine plasma peaks (1.24 µg/ml after subcutaneous and 1.15 µg/ml after oral doses) were reached 2 h following administration, the t½(β) values being 5.70 and 5.26 h, respectively. Minor epigalanthamine and galanthaminone plasma levels were detected. An almost complete urinary recovery of galanthamine and its metabolites was obtained within 72 h. The plasma AUC, Cmax, tmax and ka suggest that the subcutaneous and oral Nivalin formulations are bioequivalent.
A study on galanthamine hydrobromide (Nivalin®) pharmacokinetics was carried out on male Wistar rats following single intravenous and oral administration. Plasma samples were collected after decapitation of the animals. The drug concentrations were determined spectrophotofiuorometrically. A two-compartment open model was found to describe best the experimental data. Galanthamine has an elimination half-life of 40–50 min, a volume of distribution over 2 liters/kg, a plasma clearance of about 2 liters/h · kg and an oral bioavailability of about 65%.
The monooxygenase-mediated hydroxylations of aliphatic carbon atoms are known to be regioselective for positions alpha to heteroatoms or to pi systems (aromatic rings, carbon-carbon double bonds, carbonyl groups). Ab initio calculations (STO-3G and in some cases 4-31G) were performed on model molecules, indicating that the Mulliken overlap populations (taken as indices of electron bond densities) of Calpha-H bonds being regioselectively hydroxylated are larger than Cbeta-H and Cgamma-H overlap populations. These results support the hypothesis that metabolic C-hydroxylations occur by insertion of an activated oxygen species of electrophilic nature, probably oxene.
Analogue and digital computing techniques have been used to elucidate the pharmacokinetic parameters involved in the metabolism and excretion of diethylpropion and its metabolites in man. Rate constants for the various processes have been evaluated for the complex reaction scheme. The values of the rate constants are used as a basis for discussion of the relative importance of some of the metabolic routes.
The quantitative parameters characterizing the binding of phenylbutazone (CAS 50-33-9) to human serum albumin are determined using the circular dichroism titration method and a combined mathematical approach. The values of affinity constants obtained are in good agreement with those found in the literature. The characterization and identification of binding sites is also performed. A conclusion is derived that phenylbutazone can be used as a model compound for investigation of ligand-macromolecule interactions.
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