A homotropic two-state model and auto-antagonism

BACKGROUND: Bell-shaped and terraced dose-response relations have been observed in single ligand application for enzymes, carriers, transporters, G protein-coupled receptors as well as for other receptive units. It seems that there is still a need for new models as analytical tools for such dose-responses, especially in the light of expanding di- and multi-merization of the receptive units for functionality. RESULTS: Self-inhibition by drugs is analyzed in the frame-work of a theoretical homotropic two-state model, HOTSM. The model is a cubic reaction scheme based on a combination of conformational isomerization between two states within a receptive unit and ternary-complexing of two identical agonist molecules with the receptor. Concepts and terms related to self-inhibition are presented. HOTSM has seven independent parameters. Making a few simplifying assumptions narrows its analysis to initially look at four parameters. Some conclusions to be drawn are that a first level of spontaneous activity is solely determined by an isomerization constant, L. As ligand concentration rises, all seven parameters influence a second level of activity. At high ligand concentrations, a third level of activity is determined by only four of the seven constants, viz. the L constant and three intrinsic efficacy related constants, a, b, and d. The third level is given by 1/[1 + 1/(L·a·b·d)]. The third level may be above, at, or below the first and second levels. When the third level is above the first level, dose-responses may be bell-shaped, terraced, or reversed bell-shaped while when it is below the first level, dose-responses can attain forms of bell-shapes, reverse terraces, or reverse bell-shapes. To exemplify its use, the HOTSM is fitted to experimental dose-responses from sources in the literature. Development of the HOTSM is reviewed. CONCLUSIONS: The homotropic two-state model, HOTSM, is a novel model for analyses of dose-responses at equilibrium that are co-operative or show bell-shapes of auto-antagonism

Different quantization mechanisms in single-electron pumps driven by surface acoustic waves

We have studied the acoustoelectric current in single-electron pumps driven by surface acoustic waves. We have found that in certain parameter ranges two different sets of quantized steps dominate the acoustoelectric current versus gate-voltage characteristics. In some cases, both types of quantized steps appear simultaneously though at different current values, as if they were superposed on each other. This could indicate two independent quantization mechanisms for the acoustoelectric current.Comment: 6 pages, 3 figure

Multiple Andreev reflections in diffusive SNS structures

We report new measurements on sup-gap energy structure originating from multiple Andreev reflections in mesoscopic SNS junctions. The junctions were fabricated in a planar geometry with high transparency superconducting contacts of Al deposited on highly diffusive and surface d-doped n++-GaAs. For samples with a normal GaAs region of active length 0.3um the Josephson effect with a maximal supercurrent Ic=3mA at T=237mK was observed. The sub-gap structure was observed as a series of local minima in the differential resistance at dc bias voltages V=2D/ne with n=1,2,4 i.e. only the even sub-gap positions. While at V=2D/e (n=1) only one dip is observed, the n=2, and the n=4 sub-gap structures each consists of two separate dips in the differential resistance. The mutual spacing of these two dips is independent of temperature, and the mutual spacing of the n=4 dips is half of the spacing of the n=2 dips. The voltage bias positions of the sub-gap differential resistance minima coincide with the maxima in the oscillation amplitude when a magnetic field is applied in an interferometer configuration, where one of the superconducting electrodes has been replaced by a flux sensitive open loop.Comment: 20 pages, 7 figure

Three cases of anaphylaxis following injection of a depot corticosteroid with evidence of IgE sensitization to macrogols rather than the active steroid

We present three cases with anaphylaxis after injection of a depot corticosteroid. First, the steroid was suspected as the elicitor, but after evaluation the excipient macrogol was found to be the elicitor. One of the patients had reactions to several unrelated drugs. Increased awareness of anaphylaxis to excipients such as macrogols is needed, especially when allergy tests for the active drug is negative and in patients with a history of repeated anaphylaxis to seemingly unrelated drugs. To establish the correct diagnosis it is important to test with the exact formulation of the culprit drug, as well as all the ingredients including excipients