Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen-related apple allergy.

Background: Birch pollen-related apple allergy is among the most prevalent food allergies in adolescent/adult subjects and mainly results from sensitization to the major birch pollen allergen Bet v 1 and subsequent cross-reaction with the apple protein Mal d 1. However, specific immunotherapy with birch pollen has inconsistent effects on apple allergy.

Objective: We sought to compare the safety and efficacy of sublingual immunotherapy (SLIT) with 2 formulations containing either rMal d 1 or rBet v 1 on birch pollen-related apple allergy.

Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy.

Background: The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1.

Objectives: Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1.

Methods: Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques.

A pilot study to assess the efficacy of tariquidar to inhibit P-glycoprotein at the human blood-brain barrier with (R)-11C-verapamil and PET.

Unlabelled: Tariquidar, a potent, nontoxic, third-generation P-glycoprotein (P-gp) inhibitor, is a possible reversal agent for central nervous system drug resistance. In animal studies, tariquidar has been shown to increase the delivery of P-gp substrates into the brain by severalfold. The aim of this study was to measure P-gp function at the human blood-brain barrier (BBB) after tariquidar administration using PET and the model P-gp substrate (R)-(11)C-verapamil.

Interactions between ABC-transport proteins and the secondary Fusarium metabolites enniatin and beauvericin.

Enniatins (ENN) and beauvericin (BEA) exert cytotoxic properties. Here, we observed that their impact on Ca(2+)-homeostasis can be reversed by exogenous ATP. Thus, we investigated whether membrane-located ATP-binding cassette (ABC) transporters influence ENNs- and BEA-induced cytotoxicity.

Multispecificity of drug transporters: probing inhibitor selectivity for the human drug efflux transporters ABCB1 and ABCG2.

Multidrug resistance transporters P-glycoprotein/ABCB1 and ABCG2 limit the effect of a large number of cytostatic and cytotoxic drugs by energy-dependent efflux. In experimental models, pump inhibitors reestablish sensitivity towards these drugs. Both transporters demonstrate remarkably broad and partly overlapping substrate specificity.

Catalytic cycle of ATP hydrolysis by P-glycoprotein: evidence for formation of the E.S reaction intermediate with ATP-gamma-S, a nonhydrolyzable analogue of ATP.

Structural and biochemical studies of ATP-binding cassette (ABC) transporters suggest that an ATP-driven dimerization of the nucleotide-binding domains (NBDs) is an important reaction intermediate of the transport cycle. Moreover, an asymmetric occlusion of ATP at one of the two ATP sites of P-glycoprotein (Pgp) may follow the formation of the symmetric dimer. It has also been postulated that ADP drives the dissociation of the dimer.

Self-organizing maps for identification of new inhibitors of P-glycoprotein.

Self-organizing maps were trained to separate high- and low-active propafenone-type inhibitors of P-glycoprotein. The trained maps were subsequently used to identify highly active compounds in a virtual screen of the SPECS compound library.

Role of transmembrane domain/transmembrane domain interfaces of P-glycoprotein (ABCB1) in solute transport. Convergent information from photoaffinity labeling, site directed mutagenesis and in silico importance prediction.

Human P-glycoprotein (P-gp, ABCB1) plays an important role in the development of resistance to anticancer therapy. This ABC-transporter (ATP-binding cassette transporter) intercepts drugs at the level of the plasma membrane and effluxes them before they are able to reach their intracellular target structures. Inhibition of P-gp by low molecular weight compounds has been advocated as a concept for resensitization of cells to anticancer agents and several clinical studies in oncological patients have advanced to phase III.

Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis.

Terminal erythropoiesis is accompanied by extreme demand for iron to ensure proper hemoglobinization. Thus, erythroblasts must modify the "standard" post-transcriptional feedback regulation, balancing expression of ferritin (Fer; iron storage) versus transferrin receptor (TfR1; iron uptake) via specific mRNA binding of iron regulatory proteins (IRPs). Although erythroid differentiation involves high levels of incoming iron, TfR1 mRNA stability must be sustained and Fer mRNA translation must not be activated because iron storage would counteract hemoglobinization.

Photoaffinity labeling of P-glycoprotein.

The aim of the present review is to summarize recent progress in identifying substrate binding domains of P-glycoprotein by photoaffinity labeling. Preferred substrate binding regions have been identified using a number of photoaffinity ligands, including anthracyclines, the quinazoline iodoarylazidoprazosine (IAAP), dihydropyridines, taxanes and propafenones. These studies allowed identification of protein regions, which are involved in ligand interaction.

P-glycoprotein substrate binding domains are located at the transmembrane domain/transmembrane domain interfaces: a combined photoaffinity labeling-protein homology modeling approach.

P-glycoprotein (P-gp) is an energy-dependent multidrug efflux pump conferring resistance to cancer chemotherapy. Characterization of the mechanism of drug transport at a molecular level represents an important prerequisite for the design of pump inhibitors, which resensitize cancer cells to standard chemotherapy. In addition, P-glycoprotein plays an important role for early absorption, distribution, metabolism, excretion, and toxicity profiling in drug development.

A three-dimensional model for the substrate binding domain of the multidrug ATP binding cassette transporter LmrA.

Multidrug resistance presents a major obstacle to the treatment of infectious diseases and cancer. LmrA, a bacterial ATP-dependent multidrug transporter, mediates efflux of hydrophobic cationic substrates, including antibiotics. The substrate-binding domain of LmrA was identified by using photo-affinity ligands, proteolytic degradation of LmrA, and identification of ligand-modified peptide fragments with matrix-assisted laser desorption ionization/time of flight mass spectrometry.

Intramolecular distribution of hydrophobicity influences pharmacological activity of propafenone-type MDR modulators.

Lipophilicity is one of the major determining physicochemical descriptors for P-glycoprotein (P-gp) inhibitory activity. Recently, Pajeva and Wiese showed that in case of P-gp interaction, lipophilicity may be regarded as space-directed property. In the present study, a series of propafenone-type P-gp inhibitors with systematically varying hydrophobicity distribution within the molecules were synthesised and pharmacologically tested.

A subset of highly effective propafenone-type multidrug resistance modulators lacks effects on cardiac action potential and mechanical twitch parameters of rat papillary muscles.

In this study, we tested a series of 12 previously identified, highly effective propafenone-type multidrug resistance (MDR) modulators for their possible undesirable effects on cardiac tissue. We used rat papillary muscle preparations and quantitatively determined the potency of these substances to block action potential (AP) upstroke velocity (Vmax) and to prolong APD50. Simultaneously, the effects on isometric twitch parameters were evaluated.

Similarity based SAR (SIBAR) as tool for early ADME profiling.

Estimation of bioavailability and toxicity at the very beginning of the drug development process is one of the big challenges in drug discovery. Most of the processes involved in ADME are driven by rather unspecific interactions between drugs and biological macromolecules. Within the past decade, drug transport pumps such as P-glycoprotein (Pgp) have gained increasing interest in the early ADME profiling process.

In silico screening with benzofurane- and benzopyrane-type MDR-modulators.

Development of inhibitors of the drug efflux pump P-glycoprotein is a versatile approach to overcome multi drug resistance (MDR) in tumor therapy. In an approach to lower the conformational flexibility of the lead compound propafenone, we synthesized a set of dihydrobenzofuranes and benzopyranones. In the case of the 4 diastereomeric dihydrobenzofuranes, no significant differences in activity regarding the configuration on the side-chains at the dihydrofurane moiety (cis or trans) was observed.

Identification of ligand-binding regions of P-glycoprotein by activated-pharmacophore photoaffinity labeling and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry.

Energy dependent efflux pumps confer resistance to anticancer, antimicrobial, and antiparasitic drugs. P-glycoprotein (Pgp, ABCB1) mediates resistance to a broad spectrum of antitumor drugs. Compounds that themselves are nontoxic to cells have been shown to act as inhibitors of Pgp.