We consider a measurement of finite-frequency current fluctuations, using a resonance circuit as a model for the detector. We arrive at an expression for the measurable response in terms of the current-current correlators which differs from the standard ͑symmetrized͒ formula. The possibility of detection of vacuum fluctuations is discussed.PACS numbers: 05.40.ϩj, 07.50. Hp, 72.70.ϩm Finite-frequency ͑FF͒ current fluctuations at zero temperature ͑vacuum fluctuations, VFs͒ have been discussed for a long time 1 in connection with the analogous question of electromagnetic vacuum fluctuations. Recently there has been renewed interest in the noise at finite frequency in connection with the supposed possibility of observing the Fermi edge singularity in noninteracting 1,2 and interacting 3 systems.In the present letter we consider a realistic model for an FF measurement and show that, in a very close analogy with the electromagnetic vacuum fluctuations, a certain measurability limitation appears.There are different practical and theoretical approaches to FF measurements:1. Making repeated measurements of the instantaneous values of the current over a long time interval and later Fourier transforming the data obtained.2. Making a single measurement of the charge transmitted during a given time interval. In that case the information about the FF fluctuation appears through an integral over all frequencies. Ideally that can be done by making two measurements of the charge in the reservoir, the initial ͑during system preparation͒ and final. An alternative measurement can be made with a ''Larmor clock'' ͑the spin rotating in the magnetic field produced by the current͒; this method, which is described in Ref. 4, can perhaps be implemented.3. Making a time-averaged measurement of the response of a resonance circuit, which can be an ordinary LC element, i.e., an inductive element coupled to the quantum wire, a capacitor whose charge is the quantity to be measured as a response, and the resistance of the circuit.The last approach, we believe, is the most relevant for FF measurements.We model our detector ͑the resonator, which we will refer to as LC) by an oscillator 1

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A physiologically based kidney model was developed to analyze the renal excretion and kidney exposure of hydrophilic agents, in particular contrast media, in rats. In order to study the influence of osmolality and viscosity changes, the model mechanistically represents urine concentration by water reabsorption in different segments of kidney tubules and viscosity dependent tubular fluid flow. The model was established using experimental data on the physiological steady state without administration of any contrast media or drugs. These data included the sodium and urea concentration gradient along the cortico-medullary axis, water reabsorption, urine flow, and sodium as well as urea urine concentrations for a normal hydration state. The model was evaluated by predicting the effects of mannitol and contrast media administration and comparing to experimental data on cortico-medullary concentration gradients, urine flow, urine viscosity, hydrostatic tubular pressures and single nephron glomerular filtration rate. Finally the model was used to analyze and compare typical examples of ionic and non-ionic monomeric as well as non-ionic dimeric contrast media with respect to their osmolality and viscosity. With the computational kidney model, urine flow depended mainly on osmolality, while osmolality and viscosity were important determinants for tubular hydrostatic pressure and kidney exposure. The low diuretic effect of dimeric contrast media in combination with their high intrinsic viscosity resulted in a high viscosity within the tubular fluid. In comparison to monomeric contrast media, this led to a higher increase in tubular pressure, to a reduction in glomerular filtration rate and tubular flow and to an increase in kidney exposure. The presented kidney model can be implemented into whole body physiologically based pharmacokinetic models and extended in order to simulate the renal excretion of lipophilic drugs which may also undergo active secretion and reabsorption.

Background/Introduction Vericiguat is a soluble guanylate cyclase (sGC) stimulator, like riociguat and nelociguat, and entered clinical development in 2012. Before entering Phase 2, pharmacokinetics (PK) and pharmacodynamics (PD) of vericiguat had been studied in healthy volunteers only, whereas riociguat and nelociguat had also been studied in patients with pulmonary hypertension (PH) and left ventricular dysfunction (LVD) or biventricular chronic heart failure (HF). We hypothesised that integrating all PK/PD data from these compounds into population PK/PD (popPK/PD) and physiology-based PK (PBPK) models could be used to predict optimal and safe dose ranges of vericiguat for Phase 2b studies in patients with worsening chronic HF. This novel bridging approach was applied in one of several translational stages to accelerate the development of vericiguat (Figure 1). Purpose We used prior knowledge from other sGC stimulators in a combined PK/PD and PBPK modelling approach to directly initiate Phase 2b studies of vericiguat in patients after Phase 1 studies in healthy volunteers. Methods PK, heart rate (HR) and systemic vascular resistance (SVR) data for vericiguat, nelociguat and riociguat were used to calculate PK/PD slopes of linear models, corrected with fraction unbound percentages (2.2%, 3.6% and 3.9%, respectively), to compare potency relative to riociguat based on unbound concentrations. PK estimates for nelociguat and riociguat were derived using population PK modelling (NONMEM) from patient studies with sparse PK sampling. PBPK models informed by preclinical physicochemical and PK data as well as clinical data for vericiguat were used to predict vericiguat PK in patients with HF (PK-Sim). Exposure–response data for riociguat in patients indicated the optimal range of PD responses for vericiguat (blood pressure for safety and cardiac index for efficacy). Results Vericiguat and nelociguat had lower potency than riociguat when comparing PK/PD slopes for HR and SVR (slope ratios of 0.23–0.32 for vericiguat and 0.33–0.47 for nelociguat). Plasma concentrations of vericiguat would need to be ∼3.6 times that of riociguat for equivalent responses. In patients with PH and LVD the optimal plasma concentration range for riociguat was ∼10–100 μg/l in exposure–response and safety studies, which translates to a target exposure range of ∼90–900 μg/l for vericiguat in patients with HF. PBPK modelling showed that vericiguat 2.5 mg and 10 mg would cover the target exposure range and that 1.25 mg would be a “non-effective” dose level with respect to haemodynamics. Conclusions Our novel translational approach combining popPK/PD analyses of other sGC stimulators with PBPK modelling enabled vericiguat to move directly from Phase 1 to Phase 2b, reducing development time by ∼2 years. PK and safety results from Phase 2b (SOCRATES-REDUCED) and Phase 3 (VICTORIA) trials confirmed that use of this translational approach to predict dose ranges of vericiguat was successful. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding for this research was provided by Bayer AG, Berlin, Germany Figure 1

Abstract. We present a numerical analysis of the single particle energy spectra of ballistic condensed matter systems and compare with recent theoretical results. We show that the presence even of we& disorder induces full chaoticity on time scales larger than the elastic disorder scattering time. To disentangle the effect of boundary, respectively disorder scattering on the spectral statistics, different types of correlation functions are introduced and discussed.