How Technical Innovations May Help to Prevent Drug Shortages in Switzerland

In this work, we investigated the technical feasibility of 'on-demand' production of selected drugs to cover their demand for a time window of 90 days. We focused on two sub-processes 'automated chemical synthesis' and 'formulation in micropellets'  to enable personalized dosing. The production of drugs 'on-demand' is challenging, important, but also attractive. Switzerland could thus gain access to an additional instrument for increasing resilience for supply-critical drugs. The biggest challenge in the case study presented here is the scalability of automated chemical synthesis and the application range of micropellet formulations

Gastrin-Releasing Peptide Signaling Plays a Limited and Subtle Role in Amygdala Physiology and Aversive Memory

Links between synaptic plasticity in the lateral amygdala (LA) and Pavlovian fear learning are well established. Neuropeptides including gastrin-releasing peptide (GRP) can modulate LA function. GRP increases inhibition in the LA and mice lacking the GRP receptor (GRPR KO) show more pronounced and persistent fear after single-trial associative learning. Here, we confirmed these initial findings and examined whether they extrapolate to more aspects of amygdala physiology and to other forms of aversive associative learning. GRP application in brain slices from wildtype but not GRPR KO mice increased spontaneous inhibitory activity in LA pyramidal neurons. In amygdala slices from GRPR KO mice, GRP did not increase inhibitory activity. In comparison to wildtype, short- but not long-term plasticity was increased in the cortico-lateral amygdala (LA) pathway of GRPR KO amygdala slices, whereas no changes were detected in the thalamo-LA pathway. In addition, GRPR KO mice showed enhanced fear evoked by single-trial conditioning and reduced spontaneous firing of neurons in the central nucleus of the amygdala (CeA). Altogether, these results are consistent with a potentially important modulatory role of GRP/GRPR signaling in the amygdala. However, administration of GRP or the GRPR antagonist (D-Phe6, Leu-NHEt13, des-Met14)-Bombesin (6–14) did not affect amygdala LTP in brain slices, nor did they affect the expression of conditioned fear following intra-amygdala administration. GRPR KO mice also failed to show differences in fear expression and extinction after multiple-trial fear conditioning, and there were no differences in conditioned taste aversion or gustatory neophobia. Collectively, our data indicate that GRP/GRPR signaling modulates amygdala physiology in a paradigm-specific fashion that likely is insufficient to generate therapeutic effects across amygdala-dependent disorders

Molecular structure and physiological functions of GABA(B) receptors

GABA(B) receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABA(B) receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABA(B) system. This led to the surprising discovery that GABA(B) receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABA(B) receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABA(B) receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABA(B) receptors and the receptors for gamma-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABA(B) receptor polymorphisms to epilepsy. Significantly, the cloning of GABA(B) receptors enabled identification of the first allosteric GABA(B) receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABA(B) receptors and discuss ongoing drug-discovery efforts

Nanoparticle adhesion and removal studied by pulsed laser irradiation

The contactless removal of small particles from surfaces by irradiation with intense laser pulses dubbed laser cleaning has been used and studied for nearly two decades. Nevertheless, its applicability and the mechanisms involved are still under debate. Here we give first a brief overview on relevant processes, and then present measurements of the velocities of colloidal model particles after detachment under vacuum conditions. We also demonstrate a new Laser Cleaning approach, by which submicrometer particles are removed by laser irradiation of the rear side of the wafers. The particles are detached by an acoustic shock wave traveling to the wafer front side after laser ablation of the rear side. Not only is this promising approach capable of defect free surface cleaning, detailed studies of particle velocities versus laser fluence also allow insight into the different cleaning mechanisms involved. Furthermore, this technique could be applied to determine adhesion energies of particles in the future

Laser cleaning of particles from silicon wafers : capabilities and mechanisms

The preparation of surfaces free of particle contamination is one of the crucial prerequisites for a further increase in the integration density of ICs and for the progress in nanotechnology. Therefore the removal of sub-micron sized particles from silicon wafers is of great interest. For this purpose a variety of cleaning methods is currently under investigation.In semiconductor industry an ideal cleaning technique should be capable of removing particles with a diameter considerably below 100 nm, while a damage to the substrate has to be strictly avoided. Furthermore the process should be environmentally friendly and cost-effective. A promising approach which meets these requirements is called Laser Cleaning. So far two major approaches can be distinguished. The first one is called Dry Laser Cleaning (DLC), where the surface to be cleaned is simply irradiated by a short laser pulse [1,2,3]. In Steam Laser Cleaning (SLC) a thin layer of a liquid energy transfer medium is deposited on the surface prior to the laser pulse [1,2,4,5].In this paper we will present a short overview of these techniques followed by some of our recent results. The emphasis lies on the underlying mechanisms and an industrial applicability of both cleaning methods

Universal threshold for the steam laser cleaning of submicron spherical particles from silicon

The efficiency of the steam laser cleaning process is examined. For the investigation of the physics of particle removal from the particularly interesting surface of silicon we have deposited well-characterized spherical polymer and silica particles of different diameters ranging from several tens to hundreds of nanometers on commercial wafers. As a result of our systematic study we observe a sharp threshold of the steam cleaning process at 110 mJ/cm2 (h=532 nm, FWHMD=7 ns) which is independent of the size (for particles with diameters as small as 60 nm) and material of the particles. An efficiency above 90% after 20 cleaning steps is reached at a laser fluence of 170 mJ/cm2. Experiments with irregularly shaped alumina particles exhibit the same threshold as for spherical particles

Infrared steam laser cleaning

Steam Laser Cleaning with a pulsed infrared laser source is investigated. The infrared light is tuned to the absorption maximum of water (λ = 2.94 µm, 10 ns), whereas the substrates used are transparent (glass, silicon). Thus a thin liquid water layer condensed on top of the contaminated substrate is rapidly heated. The pressure generated during the subsequent phase explosion generates a cleaning force which exceeds the adhesion of the particles. We examine the cleaning threshold in single shot experiments for particles sized from 1 µm down to 300 nm

Laser cleaning of silicon surfaces

The continuing trend towards miniaturization of integrated circuits requires increasing effots and new concepts to clean wafer surfaces from dust particles. We report here about our studies of the "steam laser cleaning" process first described by Tam and coworkers: In order to remove sub-micron particles from a surface, first a thin liquid layer is condensed onto the substrate from the gas phase, and is subsequently evaporated momentarily by irradiating the surface with a short laser pulse. We have investigated the nucleation and growth of gas bubbles in the liquid, by which the whole process is started, with optical techniques like light scattering and surface plasmon resonance spectroscopy. The experiments indicate that the temperature where nucleation sets in is surprisingly low, which facilitates the application of this phenomenon for cleaning purposes. On the basis of these results and in order to study the cleaning effect for the particularly interesting surface of silicon in a quantitative way, we have deposited well-characterized spherical polymer and silica particles of different diameters from several ten to hundred nanometers on commercial Si wafers and have studied systematically the cleaning efficiency of the explosive evaporation process. The results show that steam laser cleaning is a promising and suitable method for removing sub-micron particles from semiconductor surfaces

Selected amino acids, dipeptides and arylalkylamine derivatives do not act as allosteric modulators at GABAB receptors.

Based on recent reports describing enhancing actions of arylalkylamines (fendiline [N-(3,3-diphenylpropyl)-alpha-methylbenzylamine] and prenylamine [N-(3,3-diphenylpropyl)-alpha-methylphenethylamine]), amino acids (L-phenylalanine, L-leucine and L-isoleucine), and dipeptides (L-Phe-Phe and L-Phe-Leu) on baclofen-induced responses in cortical slices, we have examined whether these compounds might act as positive allosteric modulators at GABA(B) receptors. Unlike the previously described allosteric GABA(B) receptor modulator CGP7930 (2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol), these compounds did not enhance GABA(B) receptor-mediated guanosine 5'-O-(3-thiotriphosphate) [GTP(gamma)35S] binding in native or recombinant cell membrane preparations. Similarly, in a competition binding assay using the antagonist radioligand [3H]CGP62349, CGP7930, but not the other compounds, enhanced the affinities of gamma-aminobutyric acid (GABA) for native GABA(B) receptors from rat brain cortex. Finally, in a cellular assay (Ca(2+) signaling in a recombinant cell line), CGP7930 was again the only compound found to enhance the GABA response. It is concluded that the arylalkylamines, amino acids and dipeptides tested do not act as allosteric modulators at native and recombinant GABA(B) receptors