Classification of anaphylaxis and utility of the EAACI Taskforce position paper on anaphylaxis in children.

Correct management and classification of anaphylaxis is mandatory. Records of emergency department (ED) visits to any of the three pediatric hospitals in Stockholm, because of reactions to foods during 2007, were identified. A retrospective analysis of clinical ED records of 371 children with 381 unique occasions of reactions to foods was performed. Symptoms/signs of reactions to foods recorded for classification of anaphylaxis were related to those presented in the EAACI Taskforce position paper on Anaphylaxis in Children (Allergy 2007; 62: 857). Forty-six different symptoms/signs of reactions to foods were retrieved. Several severe signs or symptoms from the respiratory tract and signs indicating reduced brain perfusion were not described in detail in the EAACI paper, hampering correct classification of anaphylaxis including grading of severity in our material. After modification of the EAACI classification including such signs and symptoms, we were able to classify 128 (35%) children with anaphylaxis. Seventy children (19%) did not fulfill our modified EAACI's criteria for anaphylaxis. They had been given adrenaline before or at arrival to hospital, possibly preventing anaphylaxis. Another 173 (47%) children/adolescents had neither been given adrenalin, nor fulfilled the criteria for anaphylaxis. Classification of food-induced anaphylaxis and severity grading should be built on signs and symptoms to facilitate diagnosis. The existing EAACI tool is helpful, but for Swedish children it is not quite applicable, in particular because of the lack of description of some respiratory, neurological or possible cardiovascular signs and symptoms.

Novel affinity ligands for chromatography using combinatorial chemistry.

Spatially addressable combinatorial libraries were synthesized by solution phase chemistry and screened for binding to human serum albumin. Members of arylidene diamide libraries were among the best hits found, having submicromolar binding affinities. The results were analyzed by the frequency with which particular substituents appeared among the most potent compounds. After immobilization of the ligands either through the oxazolone or the amine substituent, characterization by surface plasmon resonance showed that ibuprofen affected the binding kinetics, but phenylbutazone did not. It is therefore likely that these compounds bind to Site 2 in sub domain IIIA of human serum albumin (HSA).

Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: exploration of P2 quinazoline substituents.

Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.

Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: effect of sulfonamides P3 substituents on potency and selectivity.

Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure-activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K.