Dexmedetomidine Clearance Decreases with Increasing Drug Exposure:Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

Background: Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics. Methods: The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model. Results: A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng center dot ml(-1), the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations. Conclusions: This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng center dot ml(-1) using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines

Observation of the Dependence of Scintillation from Nuclear Recoils in Liquid Argon on Drift Field

We have exposed a dual-phase Liquid Argon Time Projection Chamber (LAr-TPC) to a low energy pulsed narrowband neutron beam, produced at the Notre Dame Institute for Structure and Nuclear Astrophysics to study the scintillation light yield of recoiling nuclei in a LAr-TPC. A liquid scintillation counter was arranged to detect and identify neutrons scattered in the LAr-TPC target and to select the energy of the recoiling nuclei. We report the observation of a significant dependence on drift field of liquid argon scintillation from nuclear recoils of 11 keV. This observation is important because, to date, estimates of the sensitivity of noble liquid TPC dark matter searches are based on the assumption that electric field has only a small effect on the light yield from nuclear recoils.Comment: v3 updated to reflect published version, including a set of plots for 49.9 keV dat

A Study of the Residual 39Ar Content in Argon from Underground Sources

The discovery of argon from underground sources with significantly less 39Ar than atmospheric argon was an important step in the development of direct-detection dark matter experiments using argon as the active target. We report on the design and operation of a low background detector with a single phase liquid argon target that was built to study the 39Ar content of the underground argon. Underground argon from the Kinder Morgan CO2 plant in Cortez, Colorado was determined to have less than 0.65% of the 39Ar activity in atmospheric argon.Comment: 21 pages, 10 figure

Search for Solar Axions Produced in p(d,3He)Ap(d,\rm{^3He})A Reaction with Borexino Detector

A search for 5.5-MeV solar axions produced in the $p+d\rightarrow\rm{^3He}+A (5.5 \rm{MeV})$ reaction was performed using the Borexino detector. The Compton conversion of axions to photons, ${\rm A}+e\rightarrow e+\gamma$; the axio-electric effect, ${\rm A}+e+Z\rightarrow e+Z$; the decay of axions into two photons, ${\rm A}\rightarrow2\gamma$; and inverse Primakoff conversion on nuclei, ${\rm A}+Z\rightarrow\gamma+Z$, are considered. Model independent limits on axion-electron ($g_{Ae}$), axion-photon ($g_{A\gamma}$), and isovector axion-nucleon ($g_{3AN}$) couplings are obtained: $|g_{Ae}\times g_{3AN}| \leq 5.5\times 10^{-13}$ and $|g_{A\gamma}\times g_{3AN}| \leq 4.6\times 10^{-11} \rm{GeV}^{-1}$ at $m_A <$ 1 MeV (90% c.l.). These limits are 2-4 orders of magnitude stronger than those obtained in previous laboratory-based experiments using nuclear reactors and accelerators.Comment: 11 pages, 7 figures, submitted to Phys.Rev.

Measurement of the solar 8B neutrino rate with a liquid scintillator target and 3 MeV energy threshold in the Borexino detector

We report the measurement of electron neutrino elastic scattering from 8B solar neutrinos with 3 MeV energy threshold by the Borexino detector in Gran Sasso (Italy). The rate of solar neutrino-induced electron scattering events above this energy in Borexino is 0.217 +- 0.038 (stat) +- 0.008 (syst) cpd/100 t, which corresponds to the equivalent unoscillated flux of (2.4 +- 0.4 (stat) +- 0.1 (syst))x10^6 cm^-2 s^-1, in good agreement with measurements from SNO and SuperKamiokaNDE. Assuming the 8B neutrino flux predicted by the high metallicity Standard Solar Model, the average 8B neutrino survival probability above 3 MeV is measured to be 0.29+-0.10. The survival probabilities for 7Be and 8B neutrinos as measured by Borexino differ by 1.9 sigma. These results are consistent with the prediction of the MSW-LMA solution of a transition in the solar electron neutrino survival probability between the low energy vacuum-driven and the high-energy matter-enhanced solar neutrino oscillation regimes.Comment: 10 pages, 8 figures, 6 table

Measurement of geo-neutrinos from 1353 days of Borexino

We present a measurement of the geo--neutrino signal obtained from 1353 days of data with the Borexino detector at Laboratori Nazionali del Gran Sasso in Italy. With a fiducial exposure of (3.69 $\pm$ 0.16) $\times$ $10^{31}$ proton $\times$ year after all selection cuts and background subtraction, we detected (14.3 $\pm$ 4.4) geo-neutrino events assuming a fixed chondritic mass Th/U ratio of 3.9. This corresponds to a geo-neutrino signal $S_{geo}$ = (38.8 $\pm$ 12.0) TNU with just a 6 $\times$ $10^{-6}$ probability for a null geo-neutrino measurement. With U and Th left as free parameters in the fit, the relative signals are $S_{\mathrm{Th}}$ = (10.6 $\pm$ 12.7) TNU and $S_\mathrm{U}$ = (26.5 $\pm$ 19.5) TNU. Borexino data alone are compatible with a mantle geo--neutrino signal of (15.4 $\pm$ 12.3) TNU, while a combined analysis with the KamLAND data allows to extract a mantle signal of (14.1 $\pm$ 8.1) TNU. Our measurement of a reactor anti--neutrino signal $S_{react}$ = 84.5$^{+19.3}_{-18.9}$ TNU is in agreement with expectations in the presence of neutrino oscillations.Comment: 9 pages, 6 figure

Muon and Cosmogenic Neutron Detection in Borexino

Borexino, a liquid scintillator detector at LNGS, is designed for the detection of neutrinos and antineutrinos from the Sun, supernovae, nuclear reactors, and the Earth. The feeble nature of these signals requires a strong suppression of backgrounds below a few MeV. Very low intrinsic radiogenic contamination of all detector components needs to be accompanied by the efficient identification of muons and of muon-induced backgrounds. Muons produce unstable nuclei by spallation processes along their trajectory through the detector whose decays can mimic the expected signals; for isotopes with half-lives longer than a few seconds, the dead time induced by a muon-related veto becomes unacceptably long, unless its application can be restricted to a sub-volume along the muon track. Consequently, not only the identification of muons with very high efficiency but also a precise reconstruction of their tracks is of primary importance for the physics program of the experiment. The Borexino inner detector is surrounded by an outer water-Cherenkov detector that plays a fundamental role in accomplishing this task. The detector design principles and their implementation are described. The strategies adopted to identify muons are reviewed and their efficiency is evaluated. The overall muon veto efficiency is found to be 99.992% or better. Ad-hoc track reconstruction algorithms developed are presented. Their performance is tested against muon events of known direction such as those from the CNGS neutrino beam, test tracks available from a dedicated External Muon Tracker and cosmic muons whose angular distribution reflects the local overburden profile. The achieved angular resolution is 3-5 deg and the lateral resolution is 35-50 cm, depending on the impact parameter of the crossing muon. The methods implemented to efficiently tag cosmogenic neutrons are also presented.Comment: 42 pages. 32 figures on 37 files. Uses JINST.cls. 1 auxiliary file (defines.tex) with TEX macros. submitted to Journal of Instrumentatio

Low-energy (anti)neutrino physics with Borexino: Neutrinos from the primary proton-proton fusion process in the Sun

The Sun is fueled by a series of nuclear reactions that produce the energy that makes it shine. The primary reaction is the fusion of two protons into a deuteron, a positron and a neutrino. These neutrinos constitute the vast majority of neutrinos reaching Earth, providing us with key information about what goes on at the core of our star. Several experiments have now confirmed the observation of neutrino oscillations by detecting neutrinos from secondary nuclear processes in the Sun; this is the first direct spectral measurement of the neutrinos from the keystone proton-proton fusion. This observation is a crucial step towards the completion of the spectroscopy of pp-chain neutrinos, as well as further validation of the LMA-MSW model of neutrino oscillations.Comment: Proceedings from NOW (Neutrino Oscillation Workshop) 201