Investigated Dose Range Research Articles

Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects

Classic psychedelics have regained interest in research and therapy. Despite the long tradition of the human use of mescaline, modern data on its dose-dependent acute effects and pharmacokinetics are lacking. Additionally, its mechanism of action has not been investigated in humans. We used a randomized, double-blind, placebo-controlled, crossover design in 16 healthy subjects (8 women) who received placebo, mescaline (100, 200, 400, and 800 mg), and 800 mg mescaline together with the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg) to assess subjective effects, autonomic effects, adverse effects, and pharmacokinetics up to 30 h after drug administration. Mescaline at doses >100 mg induced dose-dependent acute subjective effects. Mescaline increased systolic and diastolic blood pressure at doses >100 mg, with no difference between doses of 200-800 mg. Heart rate increased dose-dependently. Pharmacokinetics of mescaline were dose-proportional. Maximal concentrations were reached after approximately 2 h, and the plasma elimination half-life was approximately 3.5 h. The average duration of subjective effects increased from 6.4 to 14 h with increasing doses of 100-800 mg mescaline. Nausea and emesis were frequent adverse effects at the 800 mg dose. Co-administration of ketanserin attenuated and shortened acute effects of 800 mg mescaline to become comparable to the 100 and 200 mg doses. There were no ceiling effects of the subjective response within the investigated dose range, but tolerability was lower at the highest doses. These results may assist with dose finding for future research and suggest that acute effects of mescaline are primarily mediated by 5-HT2A receptors.

Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies.

The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single-blinded, placebo-controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1-3 h and 4-6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose-proportional pharmacokinetics for AUC but not Cmax; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose-dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1-4 h and 2-6 days after IV and SC administration, respectively. Anti-drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose-proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated.

Population pharmacokinetic-pharmacodynamic model of elinzanetant based on integrated clinical phase I and II data.

Elinzanetant is a potent and selective dual neurokin-1 (NK-1) and -3 (NK-3) receptor antagonist that is currently developed for the treatment of women with moderate-to-severe vasomotor symptoms (VMS) associated with menopause. Here, we report the development of a population pharmacokinetic (popPK) model for elinzanetant and its principal metabolites based on an integrated dataset from 366 subjects (including 197 women with VMS) collected in 10 phase I or II studies. The pharmacokinetics of elinzanetant and its metabolites could be well described by the popPK model. Within the investigated dose range of 40-160 mg, the oral bioavailability of elinzanetant was dose independent and estimated to be 36.7%. The clearance of elinzanetant was estimated to be 7.26 L/h and the central and peripheral distribution volume were 23.7 and 168 L. No intrinsic or extrinsic influencing factors have been identified in the investigated population other than the effect of a high-fat breakfast on the oral absorption of elinzanetant. The popPK model was then coupled to a pharmacodynamic model to predict occupancies of the NK-1 and NK-3 receptors. After repeated once-daily administration of the anticipated therapeutic dose of 120 mg elinzanetant, the model-predicted median receptor occupancies are >99% for NK-1 and >94.8% for NK-3 during day and night-time, indicating sustained and near-complete inhibition of both target receptors during the dosing interval.

Development and characterization of Staphylococcus aureus-hydrogel-based radiation dosimeter

In the search of innovative methods within radiation dosimetry to provide solutions to the high demanding modern ionizing radiation applications, this work proposes an original approach to combine microorganisms and gel dosimetry characteristics by adapting biotechnology and molecular biology procedures. The design of bacterial culture media and the evaluation of viability as systems for radiation dosimetry are reported. In preliminary assessments, a highly promising dose-response has been observed for samples stored at 4 °C, displaying a linear trend within the investigated dose range. This underscores a promising performance, indicating the potential utility of the system as a radiation dosimeter.

Simultaneous Double Dose Measurements Using TLD-100H

Thermoluminescent dosimeters (TLD) and optically stimulated luminescent dosimeters (OSLD) are practical, accurate, and precise tools for point dosimetry in medical physics applications. The objective of this study is to investigate the luminescence properties—both OSL and TL—of lithium fluoride (LiF) doped with magnesium (Mg), copper (Cu), and phosphorous (P) (LiF: Mg, Cu, P), commercially known as TLD-100H. The goal is to devise a methodological approach for dose measurement that allows for obtaining two independently measured dose values at each irradiation point, thereby improving accuracy and precision. The luminescence properties of TLD-100H were studied using a beta irradiation source (90Sr/90Y) integrated into the TL/OSL DA-15 automated Risø reader. This study identified the ideal experimental conditions for optimal dose evaluation and used them for dosimeter calibration across doses ranging from 0.5 to 4.0 Gy. The results demonstrated that, under optimal measurement parameters, the OSL and residual thermoluminescence (ResTL) signals—correlated to two trap systems within the dosimeter—exhibited high reproducibility, stability over multiple cycles, and high precision and accuracy (≤2%). Specifically, the OSL response showed good linear behavior across the investigated dose range, while the ResTL signal exhibited linear behavior between 0.5 and 2 Gy and sublinear behavior for doses >2 Gy.

Advanced spectroscopic investigation of colour centres in LiF crystals irradiated with monochromatic hard x-rays

Nominally-pure lithium fluoride (LiF) crystals were irradiated with monochromatic hard x-rays of energy 5, 7, 9 and 12 keV at the METROLOGIE beamline of the SOLEIL synchrotron facility, in order to understand the role of the selected x-ray energy on their visible photoluminescence (PL) response, which is used for high spatial resolution 2D x-ray imaging detectors characterized by a wide dynamic range. At the energies of 7 and 12 keV the irradiations were performed at five different doses corresponding to five uniformly irradiated areas, while at 5 and 9 keV only two irradiations at two different doses were carried out. The doses were planned in a range between 4 and 1.4 × 103 Gy (10.5 mJ cm−3 to 3.7 J cm−3), depending on the x-ray energy. After irradiation at the energies of 7 and 12 keV, the spectrally-integrated visible PL intensity of the F2 and F3 + colour centres (CCs) generated in the LiF crystals, carefully measured by fluorescence microscopy under blue excitation, exhibits a linear dependence on the irradiation dose in the investigated dose range. This linear behaviour was confirmed by the optical absorption spectra of the irradiated spots, which shows a similar linear behaviour for both the F2 and F3 + CCs, as derived from their overlapping absorption band at around 450 nm. At the highest x-ray energy, the average concentrations of the radiation-induced F, F2 and F3 + CCs were also estimated. The volume distributions of F2 defects in the crystals irradiated with 5 and 9 keV x-rays were reconstructed in 3D by measuring their PL signal using a confocal laser scanning microscope operating in fluorescence mode. On-going investigations are focusing on the results obtained through this z-scanning technique to explore the potential impact of absorption effects at the excitation laser wavelength.

Exposure-response analysis of the efficacy and safety of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with or without diabetic kidney disease

BackgroundEsaxerenone is a novel non-steroidal mineralocorticoid receptor blocker. Here, we assessed efficacy and safety exposure-response relationships of esaxerenone and its covariates and thereby justified the recommended dosage regimens, focusing on the safety benefits of up-titration regimen in patients at higher risk for increased serum potassium (sK+). MethodsThe relationships between model-derived individual esaxerenone exposure and efficacy (blood pressure [BP]) and safety (increased sK+) were evaluated using multivariate linear regression and Cox regression analyses, respectively, using data from 1453 hypertensive patients with or without diabetic kidney disease in five clinical studies. ResultsExposure-efficacy analyses demonstrated that higher exposure was linearly associated with greater BP reduction over the investigated dose range. Exposure-safety analyses showed that higher exposure was associated with a higher risk of increased sK+ under a fixed-dosing regimen; higher baseline sK+ and lower baseline estimated glomerular filtration rate (eGFR) were influential covariates. Model-based simulations suggested that fewer occurrences of increased sK+ are expected under the up-titration regimen (from 1.25 to 5 mg) relative to the fixed-dosing regimen (5 mg) in patients with different combinations of these covariates. ConclusionsThe exposure-response analyses supported the esaxerenone recommended doses and the safety benefits of using the up-titration regimen.

Synthesis, characterization and thermoluminescence properties of LiCaPO4 phosphor for ionizing radiation dosimetry

Many minerals and compounds show thermoluminescence (TL) properties but only a few of them can meet the requirements of an ideal dosimeter. Several phosphate materials have been studied for low-dose dosimetryin recent times. Among the various phosphates, ABPO4-type material shows interesting TL properties. In this study, an ABPO4-type (A = Lithium, B=Calcium) phosphor is synthesized using a modified solid-state diffusion method. Temperature is maintained below 800 °C in every step of phosphor preparation to obtain the pure phase of Lithium calcium phosphate (LiCaPO4). The purpose of this work is to synthesize LiCaPO4 using a simple method, examine its structural and luminescence properties in order to gain a deeper understanding of its TL characteristics. The general TL properties, such as TL glow curve, dose linearity, sensitivity, and fading, are investigated. Additionally, this study aims to determine various kinetic parameters through Glow Curve Deconvolution (GCD) method using the Origin Lab software together with the Chen model. XRD analysis confirmed the phase purity of the phosphor with a rhombohedral structure. Lattice parameters, unit cell volume, grain size, dislocated density, and microstrain were also calculated from XRD data. Raman analysis and Fourier Transform Infrared analysis were used to collect information about molecular bonds, vibrations, identity, and structure of the phosphor. To investigate TL properties and associated kinetic parameters, the phosphor was irradiated with 6.0 MV (photon energy) and 6.0 MeV (electron energy) from a linear accelerator for doses ranging from 0.5 Gy to 6.0 Gy. For both photon and electron energy, TL glow curves have two identical peaks near 200 °C and 240 °C.The TL glow curves for 0.5 Gy–6 Gy are deconvoluted, then fitted with the appropriate model and then calculated the kinetic parameters. Kinetic parameters such as geometric factor (μg), order of kinetics, activation energy (E), and frequency factor (s) are obtained from Chen's peak shape method. The dose against the TL intensity curve shows that the response is almost linear in the investigated dose range. For photon and electron energy, the phosphor is found to be the most sensitive at 2.0 Gy and 4.0 Gy, respectively. The phosphor shows a low fading and after 28 days of exposure, it shows a signal loss of better than 3%. The studied TL properties suggest the suitability of LiCaPO4 in radiation dosimetry and associated fields.

Assessing QTc Effects of Vericiguat Using Two Different Concentration-QTc Modeling Approaches.

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure. A dedicated QTc study in patients with chronic coronary syndromes demonstrated no clinically relevant QTc effect of vericiguat for exposures across the therapeutic dose range (2.5-10 mg). Interval prolongation concentration-QTc (C-QTc) modeling was performed to complement the statistical evaluations of QTc in the dedicated QTc study. Individual time-matched, baseline- and placebo-corrected Fridericia-corrected QT interval values (ΔΔQTcF) were derived. Two approaches for ΔΔQTcF calculation were investigated: (1) ΔΔQTcF correction with data from a single baseline (as in the primary statistical analysis); and (2) ΔΔQTcF correction with a modeled baseline (considering all available individual non-treatment baselines). The ΔΔQTcF values were related to observed vericiguat concentrations with linear mixed-effects modeling. For both modeling approaches, a positive relationship was found between ΔΔQTcF and vericiguat concentration; however, the slope for the single-baseline approach was not statistically significant, whereas the slope from the modeled-baseline approach was statistically significant. The upper bound of the two-sided 90% confidence interval for model-derived QTc was <10 ms at the highest observed exposure (745 μg/L; investigated dose range 2.5-10 mg). By applying a single-baseline approach and a modeled-baseline approach that integrated all available QTc data across doses to characterize the QTc prolongation potential, this study showed that vericiguat 2.5-10mg is not associated with clinically relevant QTc effects, in line with the conclusion from the primary statistical analysis. ClinicalTrials.gov NCT03504982.

Gamma, E-Beam and X-ray Irradiations on PE/EVOH/PE Multilayer Film: An Industrial Point of View Regarding the Impact on Mechanical Properties.

X-ray and electron-beam (E-beam) sterilization technologies were assessed to supplement gamma sterilization, the most common radiation technology used today for biopharmaceutical product sterilization. The mechanical properties of a PE/EVOH/PE film were studied using tensile tests and dynamical mechanical analysis after each irradiation technology (i.e., gamma, electron beam and X-ray irradiations). The effects of each irradiation were compared using two statistical methods. The results indicate that the three irradiation technologies induce no difference in mechanical properties in the investigated dose range for this material.

First‐in‐Human (FIH), Single‐ and Multiple‐Ascending‐Dose (SAD/MAD) studies in healthy subjects of E2511, a novel tropomyosin receptor kinase a (TrkA) positive allosteric modulator (PAM)

AbstractBackgroundCholinergic innervation is affected in multiple neurodegenerative diseases associated with cognitive dysfunction. Loss of cholinergic neurons in Alzheimer’s disease (AD) is correlated with cognitive impairment. Nerve growth factor (NGF) plays a major role in the maintenance and function of cholinergic neurons. The activation of NGF‐induced trophic signaling via TrkA could be a promising therapy for neurodegenerative diseases including AD. E2511 is a novel small molecule TrkA biased PAM that has shown reinnervative effects on cholinergic neurons in nonclinical studies (without NGF‐associated hyperalgesia). The main objectives of the E2511 FIH Phase 1 studies (SAD [completed] and MAD [ongoing]) are to evaluate the safety, tolerability and pharmacokinetics in healthy subjects.Methods: Both SAD and MAD are randomized, double‐blind and placebo‐controlled studies. The SAD evaluated 5 cohorts (n = 8/cohort) in adults and 1 cohort in elderly subjects (n = 5). Food effect was evaluated in one SAD cohort. Safety was evaluated through the review of adverse events, physical examinations, clinical laboratory tests, vital signs, electrocardiogram and electroencephalograms. Blood samples were collected for determination of plasma E2511 concentrations. Repeat dosing with E2511 (once daily for 14 days) is under evaluation in the MAD study.Results: Single doses of E2511 were safe and well‐tolerated across the investigated doses in adult and elderly subjects. There were no dose‐dependent nor severe treatment‐emergent adverse events (TEAEs). There were no clinically significant changes in the evaluated safety parameters on E2511 compared to placebo. Pharmacokinetic results show that E2511 was rapidly absorbed (tmax: 1 hour). Plasma half‐life was 3.2 hours. Plasma exposures (Cmax and AUC) increased dose proportionally over the investigated dose range. Food led to a decrease of 19% in Cmax and 15% in AUC compared to fasted conditions. Plasma exposures in elderly and younger adult subjects were comparable. Evaluation of E2511 safety, tolerability and PK/PD following multiple doses is ongoing.ConclusionE2511 presented an adequate safety and PK profile in healthy adults and elderly subjects. These results support further development of E2511 as a disease‐modifying therapy for neurodegenerative diseases.

Optical characterization of lithium fluoride thin-film imaging detectors for monochromatic hard X-rays

Lithium fluoride (LiF) crystals and thin films have been successfully investigated as X-ray imaging detectors based on optical reading of visible photoluminescence emitted by stable radiation-induced F2 and F+ 3 colour centres. In this work, the visible photoluminescence response of optically-transparent LiF film detectors of three different thicknesses, grown by thermal evaporation on Si(100) substrates and irradiated with monochromatic 7 keV X-rays at several doses in the range between 13 and 4.5 × 103 Gy, was carefully investigated by fluorescence optical microscopy. For all the film thicknesses, the photoluminescence response linearly depends on the irradiation dose in the investigated dose range. The lowest detected dose, delivered to the thinnest LiF film, only 0.5 μm thick, is estimated 13 Gy. Edge-enhancement imaging experiments, conducted by irradiating LiF film detectors at the same energy placing an Au mesh in front of them at a distance of 15 mm, allowed estimating a spatial resolution of (0.38 ± 0.05) μm, which is comparable to the microscope one. This very high spatial resolution in LiF film radiation detectors based on colour centres photoluminescence is combined with the availability of a wide field of view on large areas.

Radiolytic evaluation of acetohydroxamic acid (AHA) under biphasic (HNO3:n-dodecane and TBP/DEHBA/DEHiBA) used nuclear fuel reprocessing conditions

Acetohydroxamic acid (AHA) has been proposed as a substitute for hydrazine-stabilized reductants for the selective separation of plutonium and neptunium from co-extracted uranium during the reprocessing of used nuclear fuel. However, limited information exists for the chemical behavior of AHA in ionizing radiation fields, especially under representative biphasic reprocessing solvent system conditions. Here we present a systematic gamma irradiation study on the radiolytic integrity of AHA in aqueous nitric acid solutions (0.2 M HNO3) in contact with an organic phase, comprising current (tri-butyl phosphate) and next generation (N,N-di-(2-ethylhexyl)butyramide and N,N-di-(2-ethylhexyl)isobutyramide) reprocessing ligands dissolved in n-dodecane diluent. Biphasic AHA irradiations exhibited negligible effect of the organic phase on the rate of AHA radiolysis—affording an average pseudo dose constant of d' = (−58.66 ± 6.10) × 10−4 kGy−1—and subsequent formation of the predominant degradation products (hydroxylamine and acetic acid), relative to complementary single-phase systems. The radiolysis of AHA was found to have negligible impact on ligand degradation rates: G(TBP) = −0.038 ± 0.002 μmol J−1, G(DEHBA) = −0.117 ± 0.004 μmol J−1, and G(DEHiBA) = −0.102 ± 0.003 μmol J−1. These observations demonstrate that the radiolytic transients and steady-state degradation products generated in either phase have limited capacity for migrating across the aqueous-organic interface to undergo subsequent chemistry within the investigated dose range (≤110 kGy). These findings support the substitution of AHA into advanced reprocessing flowsheets.

Safety, tolerability, and pharmacokinetics of an anti-LAG-3 antibody SHR-1802 in patients with advanced solid tumors: a phase I dose-escalation and dose-expansion study.

Lymphocyte-activation gene 3 (LAG-3), a checkpoint molecule contributing to immune suppressive microenvironment, is regarded as a promising target in cancer treatment. SHR-1802 is a novel anti-LAG-3 monoclonal antibody. To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SHR-1802. A phase I dose-escalation and expansion trial of SHR-1802 in patients with advanced solid tumors. Patients with confirmed advanced solid tumors who failed previous standard-of-care or for whom no effective therapy was available were enrolled to receive SHR-1802 once every 21-day cycle. Dose escalation was performed in an accelerated titration design followed by a 3 + 3 scheme at escalating doses from 0.3 to 10 mg/kg. On the basis of results from dose-escalation phase, one or two dose levels were expanded to establish the recommended phase II dose (RP2D). The primary end points were dose-limiting toxicity (DLT) and RP2D. Between 01 July 2020, and 07 September 2021, 28 patients were enrolled. No DLTs were observed, and all doses investigated were well tolerated. Treatment-related adverse events occurred in 20 patients (71.4%), all grade 1 or 2, with the most common ones being anemia (14.3%), asthenia (14.3%), electrocardiogram QT prolonged (14.3%), followed by increased blood fibrinogen (10.7%), infusion-related reaction (10.7%), and hypoalbuminemia (10.7%). No adverse event-related discontinuation occurred. Three patients died from adverse events, but none of the deaths were deemed related to study treatment. SHR-1802 exposure enhanced with the increasing doses in a greater than dose-proportional manner over the investigated dose range. The disease control rate was 32.0% (95% CI 14.9%-53.5%). The median progression-free survival was 2.0 months (95% CI 1.2-6.1). SHR-1802 demonstrated a tolerable safety profile and preliminary antitumor activity in patients with advanced solid tumors. Further studies with larger sample size and in combination forms are warranted for future clinical application. NCT04414150.

Defects and structural changes of graphite-rich media subjected to low-level neutron doses for radiation dosimetry

Using commercially available, 0.3 mm thick rod-shaped, highly uniform 2B and HB grade polymer pencil lead graphite (PPLG), and subjected to a low-level neutron dose range of 2–10 Gy, a comprehensive understanding of radiation-induced effects have been achieved. The thermoluminescence (TL) and photoluminescence (PL) dose dependency, as well as changes in Raman spectroscopic characteristics, have been studied in order to understand the nature and distribution of defects in its crystal lattice structures that produce the luminescence signal. The atomic spacing, lattice constant, and the degree of structural order of the irradiated samples have been the primary focuses of the X-ray diffraction (XRD) study, which has then been followed by crystallite size calculations. The findings make it abundantly evident that neutron irradiation of different doses leads to some structural alteration in the studied sample at the microscopic level. Within the investigated dose range, all of the samples displayed an excellent linear response, with the sensitivity of the 2B grade PPLG being significantly higher than that of the HB. The findings show that the PPLG can be employed as a dosimetric medium for neutron radiation field. PPLG can provide a low-cost, highly effective system for researching radiation-driven changes in carbon, and all results anticipate 2B grade of PPLG to be a valuable material for new generation radiation dosimetry.

A Practical Method for EPR Dosimetry Using Alanine Powder.

This work investigates alanine powder, an inexpensive and versatile material compared to alanine pellets, as a standardized dosimeter for the alanine-EPR system using a Bruker EMX-Micro spectrometer. The feasibility of this method was investigated, and a calibration curve was produced using 40 dosimeters, which were prepared by tightly packing DL-alanine powder in polypropylene microcentrifuge tubes. The dosimeters were irradiated to doses ranging from 0.2-20 Gy using a 60 Co source. A dosimeter handling and measurement protocol was established for all dosimeters. The dosimetric signal was evaluated by measuring the peak-to-peak height of the central resonance peak, and the dose response of alanine powder dosimeters showed a linear behavior in the investigated dose range with relative errors below 13%. Measurement repeatability and reproducibility were tested to show the errors associated with sample placement in the cavity and with the overall measurement method, with both tests showing relative errors below 7%. As an inexpensive material compared to pellet dosimeters, alanine powder has a strong potential to be used as a standardized material for radiation dosimetry applications. The scope of this work is to present an effective and comprehensive methodology with accompanying analysis scripts for dosimetry with alanine powder that is useful in a wide range of applications and dose requirements.

Effects of X-Rays, Electron Beam, and Gamma Irradiation on Chemical and Physical Properties of EVA Multilayer Films

Gamma-ray irradiation, using the cobalt-60 isotope, is the most common radiation modality used for medical device and biopharmaceutical products sterilization. Although X-ray and electron-beam (e-beam) sterilization technologies are mature and have been in use for decades, impediments remain to switching to these sterilization modalities because of lack of data on the resulting radiation effects for the associated polymers, as well as a lack of education for manufacturers and regulators on the viability of these sterilization alternatives. For this study, the compatibility of ethylene vinyl acetate (EVA) multilayer films with different ionizing radiation sterilization (X-ray, e-beam, and gamma irradiation) is determined by measuring chemical and physical film properties using high performance liquid chromatography, differential scanning calorimetry, Fourier-Transform InfraRed spectroscopy (FTIR), surface energy measurement, and electron spin resonance techniques. The results indicate that the three irradiation modalities induce no differences in thermal properties in the investigated dose range. Gamma and X-Ray irradiations generate the same level of reactive species in the EVA multilayer film, whereas e-beam generates a reduced quantity of reactive species.

Target engagement of the first-in-class CXCR7 antagonist ACT-1004-1239 following multiple-dose administration in mice and humans

Antagonism of the chemokine receptor CXCR7 has shown promising effects in diverse disease areas through modulation of its ligands, CXCL11 and CXCL12. Preclinical data of the first-in-class CXCR7 antagonist, ACT-1004-1239, showed efficacy in animal models of multiple sclerosis and acute lung injury. In healthy humans, single-dose administration of ACT-1004-1239 revealed a favorable clinical profile. Here, we report the target engagement of ACT-1004-1239 in healthy mice and humans after multiple doses using CXCL11 and CXCL12 as biomarkers. In addition, safety/tolerability, concentration-QTc relationship, and pharmacokinetics (PK) were assessed in a randomized, double-blind, placebo-controlled Phase 1 clinical study. Multiple-dose ACT-1004-1239 dose-dependently increased CXCL12 plasma concentration across the investigated dose range in mice and humans (mice: 1–100 mg/kg b.i.d.; humans: 30–200 mg o.d.) when compared to vehicle/placebo demonstrating target engagement. Mouse and human PK/PD models predicted that CXCL12 concentration approached a plateau within these dose ranges. In humans, ACT-1004-1239 was rapidly absorbed (tmax: 1.75–3.01 h) and the terminal t1/2 was approximately 19 h. Steady-state conditions were reached by Day 3 with an accumulation index of 1.2. Female subjects had overall higher exposure compared to males. Multiple-dose ACT-1004-1239 was well tolerated up to 200 mg once daily in humans. There was no evidence of ACT-1004-1239-mediated QTc interval prolongation. Overall, multiple oral doses of ACT-1004-1239 showed target engagement with CXCR7 in healthy mice and humans, therefore, assessment of CXCL12 as translational tool for further investigations in patients is warranted. Favorable safety/tolerability and PK profiles allow for further clinical development.

Evaluation of the in-situ performance of neutron detectors based on EJ-426 scintillator screens for spent fuel characterization

The reliable detection of neutrons in a harsh gamma-ray environment is an important aspect of establishing non-destructive methods for the characterization of spent nuclear fuel. In this study, we present results from extended in-situ monitoring of detector systems consisting of commercially available components: EJ-426, a 6Li-enriched solid-state scintillator material sensitive to thermal neutrons, and two different types of Hamamatsu photomultiplier tubes (PMT). Over the period of eight months, these detectors were operated in close vicinity to spent nuclear fuel stored at the interim storage facility CLAB, Oskarshamn, Sweden. At the measurement position the detectors were continuously exposed to an estimated (moderated) neutron flux of approx. 280n/scm2 and a gamma-ray dose rate of approximately 6Sv/h.Using offline software algorithms, neutron pulses were identified and characterized in the data. Over the entire investigated dose range of up to 35kGy, the detector systems were functioning and were delivering detectable neutron signals. Their performance as measured by the number of identified neutrons degrades down to about 30% of the initial value. Investigations of the irradiated components suggest that this degradation is a result of reduced optical transparency of the involved materials as well as a reduction of PMT gain due to the continuous high currents. Increasing the gain of the PMT through step-ups of the applied high voltage allowed to partially compensate for this loss in detection sensitivity even when the detectors were highly irradiated.The integrated neutron fluence during the measurement was experimentally verified to be in the order of 5×109ncm−2. The results were interpreted with the help of MCNP6.2 simulations of the setup and the neutron flux.

On the dose dependence prior and after stimulation with visible light of E’ and Al-hole centres in sedimentary quartz: Correlation and mechanisms

E′ and Al-hole centres are some of the most common and abundant paramagnetic defects in sedimentary quartz. Here we investigate the dose dependence of these defects before and after exposure to light by electron spin resonance (ESR). Unlike the Al-hole centre, known to have only radiation-induced formation mechanisms, the E′ centre seems to possess a response to gamma dose characterised by predominantly radiation-induced annihilation at lower doses (up to about 1000 Gy) and a predominantly radiation-induced formation at higher doses, at least in the investigated dose range (up to 40 kGy) and samples. We propose these dose response mechanisms to be governed by electron trapping by E′ centre itself and by hole trapping by the oxygen deficiency centre (ODC), that seems to be the main precursor of E’ centre. We show that the ESR signals of both defects are linearly correlated during their formation as well as during their dissociation under both irradiation and sunlight exposure. The amount of E′ formed after light exposure was found to follow a saturating exponential behaviour as function of the annihilated Al-hole concentration in respect to dose, saturation being reached for doses of about 1000 Gy, probably due to the exhaustion of ODC population. As such, we propose that the origin of the unbleachable part of the Al-hole signal resides in the availability of oxygen deficiency centres which is also dependent on the accumulated gamma dose.