Variation of the baseline characteristics and treatment parameters over time: an analysis of 15 years of growth hormone replacement in adults in the German KIMS database

The purpose of this study is to examine potential implications of changes in the approach to adult growth hormone (GH) replacement (GHR) over the last 15 years. Therefore, we analysed the German KIMS database as one of the largest single country pharmacoepidemiological databases on adult GH deficiency (GHD). Based on the date of their first GH application patients were assigned to three intervals (1995–1999, 2000–2004, 2005–2009). A multivariate analysis of variance with interval and sex as independent variables was conducted. Differences were analysed with respect to IGF-I standard deviation score (SDS), quality of life, latency between GHD diagnosis and first GH dose, body mass index, waist–hip ratio, lipid profile, and GH dose. All analyses were conducted at baseline, 1 year, and 3 years of GHR. We detected significant associations between time interval and patient characteristics at baseline and with treatment effects. Recently, patients with less severe GHD (mean IGF-I SDS: −2.1, −1.6, −1.0 in the 1st, 2nd and 3rd interval; p = 0.000) are treated with lower GH starting doses (mean 0.30, 0.19, 0.21 mg/day in the 1st, 2nd and 3rd interval; p = 0.000). In the first time interval, IGF-I SDS was not normalized in females after 3 years of GHR. The results of our analysis demonstrate prominent changes in patient characteristics and handling of GHR. They highlight that approach to therapy and patient inclusion criteria change over time and may represent an important confounder for any analysis in epidemiological surveillance surveys.

     

Hexamethylene diisocyanate (HDI) vapor reactivity with glutathione and subsequent transfer to human albumin

IntroductionAirway fluid glutathione (GSH) reactivity with inhaled vapors of diisocyanate, a common occupational allergen, is postulated to be a key step in exposure-induced asthma pathogenesis.MethodsA mixed (vapor/liquid) phase exposure system was used to model the in vivo reactivity of inhaled HDI vapor with GSH in the airway fluid. HDI–GSH reaction products, and their capacity to transfer HDI to human albumin, were characterized through mass spectrometry and serologic assays, using HDI-specific polyclonal rabbit serum.ResultsHDI vapor exposure of 10 mM GSH solutions resulted in primarily S-linked, bis(GSH)–HDI reaction products. In contrast, lower GSH concentrations (100 μM) resulted in mainly mono(GSH)–HDI conjugates, with varying degrees of HDI hydrolysis, dimerization and/or intra-molecular cyclization, depending upon the presence/absence of H₂PO₄^?/HPO₄^2? and Na⁺/Cl^? ions. The ion composition and GSH concentration of the fluid phase, during HDI vapor exposure, strongly influenced the transfer of HDI from GSH to albumin, as did the pH and duration of the carbamoylating reaction. When carbamoylation was performed overnight at pH 7, 25 of albumin’s lysines were identified as potential sites of conjugation with partially hydrolyzed HDI. When carbamoylation was performed at pH 9, more rapid (within 3 h) and extensive modification was observed, including additional lysine sites, intra-molecular cross-linkage with HDI, and novel HDI–GSH conjugation.ConclusionsThe data define potential mechanisms by which the levels of GSH, H₂PO₄^?/HPO₄^2?, and/or other ions (e.g. H⁺/OH^?, Na⁺, Cl^?) affect the reactivity of HDI vapor with self-molecules in solution (e.g. airway fluid), and thus, might influence the clinical response to HDI respiratory tract exposure.