Publications by authors named "Martin Bauer"

156 Publications

Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [C]Metoclopramide.

Mol Imaging Biol 2021 04 22;23(2):180-185. Epub 2021 Jan 22.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

Purpose: To assess in healthy volunteers the whole-body distribution and dosimetry of [C]metoclopramide, a new positron emission tomography (PET) tracer to measure P-glycoprotein activity at the blood-brain barrier.

Procedures: Ten healthy volunteers (five women, five men) were intravenously injected with 387 ± 49 MBq of [C]metoclopramide after low dose CT scans and were then imaged by whole-body PET scans from head to upper thigh over approximately 70 min. Ten source organs (brain, thyroid gland, right lung, myocardium, liver, gall bladder, left kidney, red bone marrow, muscle and the contents of the urinary bladder) were manually delineated on whole-body images. Absorbed doses were calculated with QDOSE (ABX-CRO) using the integrated IDAC-Dose 2.1 module.

Results: The majority of the administered dose of [C]metoclopramide was taken up into the liver followed by urinary excretion and, to a smaller extent, biliary excretion of radioactivity. The mean effective dose of [C]metoclopramide was 1.69 ± 0.26 μSv/MBq for female subjects and 1.55 ± 0.07 μSv/MBq for male subjects. The two organs receiving the highest radiation doses were the urinary bladder (10.81 ± 0.23 μGy/MBq and 8.78 ± 0.89 μGy/MBq) and the liver (6.80 ± 0.78 μGy/MBq and 4.91 ± 0.74 μGy/MBq) for female and male subjects, respectively.

Conclusions: [C]Metoclopramide showed predominantly renal excretion, and is safe and well tolerated in healthy adults. The effective dose of [C]metoclopramide was comparable to other C-labeled PET tracers.
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http://dx.doi.org/10.1007/s11307-021-01582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910245PMC
April 2021

Impaired Clearance From the Brain Increases the Brain Exposure to Metoclopramide in Elderly Subjects.

Clin Pharmacol Ther 2021 Mar 14;109(3):754-761. Epub 2020 Oct 14.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

The antiemetic and gastroprokinetic drug metoclopramide is a weak substrate of the blood-brain barrier (BBB) efflux transporter P-gp and displays central nervous system (CNS) side effects (i.e., extrapyramidal symptoms and tardive dyskinesia) caused by dopamine D receptor blockade in the basal ganglia. These side effects occur with a higher incidence in elderly people. We used positron emission tomography to assess the brain distribution of [ C]metoclopramide in young (n = 11, 26 ± 3 years) and elderly (n = 7, 68 ± 9 years) healthy men both after administration of a microdose (9 ± 7 µg) and a microdose co-injected with a therapeutic dose of unlabeled metoclopramide (10 mg). For both doses, elderly subjects had a significantly higher total volume of distribution (V ) of [ C]metoclopramide in the basal ganglia than young subjects (microdose: +26%, therapeutic dose: +41%). Increases in V (= K /k ) were caused by significant decreases in the transfer rate constant of [ C]metoclopramide from brain into plasma (k , microdose: -18%, therapeutic dose: -30%), whereas the distributional clearance from plasma into brain (K ) remained unaltered. This reduction in the clearance of [ C]metoclopramide (k ) from the brains of elderly subjects may be caused by an age-related decrease in the activity of P-gp at the BBB and may contribute to the higher incidence of CNS side effects of metoclopramide in the aged population. Our data suggest that an age-associated decrease in the clearance properties of the BBB may modulate the CNS effects or side effects of clinically used P-gp substrates.
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http://dx.doi.org/10.1002/cpt.2052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983943PMC
March 2021

Association of dopamine D receptor binding potential measured using PET and [C]-(+)-PHNO with post-mortem DRD gene expression in the human brain.

Neuroimage 2020 12 17;223:117270. Epub 2020 Aug 17.

Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.

Open access post-mortem transcriptome atlases such as the Allen Human Brain Atlas (AHBA) can inform us about mRNA expression of numerous proteins of interest across the whole brain, while in vivo protein binding in the human brain can be quantified by means of neuroreceptor positron emission tomography (PET). By combining both modalities, the association between regional gene expression and receptor distribution in the living brain can be approximated. Here, we compare the characteristics of D and D dopamine receptor distribution by applying the dopamine D receptor agonist radioligand [C]-(+)-PHNO and human gene expression data. Since [C]-(+)-PHNO has a higher affinity for D compared to D receptors, we hypothesized that there is a stronger relationship between D non-displaceable binding potentials (BP) and D mRNA expression. To investigate the relationship between D BP and mRNA expression of DRD2 and DRD3 we performed [C]-(+)-PHNO PET scans in 27 healthy subjects (12 females) and extracted gene expression data from the AHBA. We also calculated D/D mRNA expression ratios to imitate the mixed D signal of [C]-(+)-PHNO. In accordance with our a priori hypothesis, a strong correlation between [C]-(+)-PHNO and DRD3 expression was found. However, there was no significant correlation with DRD2 expression. Calculated D/D mRNA expression ratios also showed a positive correlation with [C]-(+)-PHNO binding, reflecting the mixed D signal of the radioligand. Our study supports the usefulness of combining gene expression data from open access brain atlases with in vivo imaging data in order to gain more detailed knowledge on neurotransmitter signaling.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117270DOI Listing
December 2020

Public communication by research institutes compared across countries and sciences: Building capacity for engagement or competing for visibility?

PLoS One 2020 8;15(7):e0235191. Epub 2020 Jul 8.

National Sun Yat-sen University, Kaohsiung, Taiwan.

Leading academic institutions, governments, and funders of research across the world have spent the last few decades fretting publicly about the need for scientists and research organisations to engage more widely with the public and be open about their research. While a global literature asserts that public communication has changed from a virtue to a duty for scientists in many countries and disciplines, our knowledge about what research institutions are doing and what factors drive their 'going public' is very limited. Here we present the first cross-national study of N = 2,030 research institutes within universities and large scientific organisations in Brazil, Germany, Italy, Japan, the Netherlands, Portugal, the United Kingdom, and the United States of America. We find that institutes embrace communication with non-peers and do so through a variety of public events and traditional news media-less so through new media channels-and we find variation across countries and sciences, yet these are less evident than we expected. Country and disciplinary cultures contribute to the level of this communication, as do the resources that institutes make available for the effort; institutes with professionalised staff show higher activity online. Future research should examine whether a real change in the organisational culture is happening or whether this activity and resource allocation is merely a means to increase institutional visibility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235191PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343166PMC
September 2020

Axionlike Particles, Lepton-Flavor Violation, and a New Explanation of a_{μ} and a_{e}.

Phys Rev Lett 2020 May;124(21):211803

Theoretical Physics Department, CERN, 1211 Geneva, Switzerland.

Axionlike particles (ALPs) with lepton-flavor-violating couplings can be probed in exotic muon and tau decays. The sensitivity of different experiments depends strongly on the ALP mass and its couplings to leptons and photons. For ALPs that can be resonantly produced, the sensitivity of three-body decays such as μ→3e and τ→3μ exceeds by many orders of magnitude that of radiative decays like μ→eγ and τ→μγ. Searches for these two types of processes are therefore highly complementary. We discuss experimental constraints on ALPs with a single dominant lepton-flavor-violating coupling. Allowing for one or more such couplings offers qualitatively new ways to explain the anomalies related to the magnetic moments of the muon or the electron. The explanation of both anomalies requires lepton-flavor-nonuniversal or lepton-flavor-violating ALP couplings.
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http://dx.doi.org/10.1103/PhysRevLett.124.211803DOI Listing
May 2020

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D receptor agonist radioligand study.

Transl Psychiatry 2020 01 8;10(1). Epub 2020 Jan 8.

Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D receptor agonist radioligand [C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.
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http://dx.doi.org/10.1038/s41398-019-0681-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026156PMC
January 2020

The Effect of Orally Administered Dronabinol on Optic Nerve Head Blood Flow in Healthy Subjects-A Randomized Clinical Trial.

Clin Pharmacol Ther 2020 07 23;108(1):155-161. Epub 2020 Feb 23.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

It has been hypothesized that besides its intraocular pressure (IOP) lowering potential, tetrahydrocannabinol (THC) may also improve ocular hemodynamics. The aim of the present study was to investigate whether single oral administration of dronabinol, a synthetic THC, alters optic nerve head blood flow (ONHBF) and its regulation in healthy subjects. The study was carried out in a randomized, placebo-controlled, double-masked, two-way crossover design in 24 healthy subjects. For each study participant, 2 study days were scheduled, on which they either received capsules containing 5 mg dronabinol or placebo. ONHBF was measured with laser Doppler flowmetry at rest and while the study participants performed isometric exercise for 6 minutes to increase mean arterial blood pressure (MAP). This was repeated 1 hour after drug intake. Ocular perfusion pressure (OPP) was calculated as 2/3MAP-IOP. Dronabinol was well tolerated and no cannabinoid-related psychoactive effects were reported. Neither administration of dronabinol nor placebo had an effect on IOP, MAP, or OPP. In contrast, dronabinol significantly increased ONHBF at rest by 9.5 ± 8.1%, whereas placebo did not show a change in ONHBF (0.3 ± 7.4% vs. baseline, P < 0.001 between study days). Dronabinol did not alter the autoregulatory response of ONHBF to isometric exercise. In conclusion, the present data indicate that low-dose dronabinol increases ONHBF in healthy subjects without affecting IOP, OPP, or inducing psychoactive side effects. In addition, dronabinol does not alter the autoregulatory response of ONHBF to an experimental increase in OPP. Further studies are needed to investigate whether this effect can also be observed in patients with glaucoma.
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http://dx.doi.org/10.1002/cpt.1797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325313PMC
July 2020

Assessment of brain delivery of a model ABCB1/ABCG2 substrate in patients with non-contrast-enhancing brain tumors with positron emission tomography.

EJNMMI Res 2019 Dec 12;9(1):110. Epub 2019 Dec 12.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

Background: P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters expressed at the blood-brain barrier which effectively restrict the brain distribution of the majority of currently known anticancer drugs. High-grade brain tumors often possess a disrupted blood-brain tumor barrier (BBTB) leading to enhanced accumulation of magnetic resonance imaging contrast agents, and possibly anticancer drugs, as compared to normal brain. In contrast to high-grade brain tumors, considerably less information is available with respect to BBTB integrity in lower grade brain tumors.

Materials And Methods: We performed positron emission tomography imaging with the radiolabeled ABCB1 inhibitor [C]tariquidar, a prototypical ABCB1/ABCG2 substrate, in seven patients with non-contrast -enhancing brain tumors (WHO grades I-III). In addition, ABCB1 and ABCG2 levels were determined in surgically resected tumor tissue of four patients using quantitative targeted absolute proteomics.

Results: Brain distribution of [C]tariquidar was found to be very low across the whole brain and not significantly different between tumor and tumor-free brain tissue. Only one patient showed a small area of enhanced [C]tariquidar uptake within the brain tumor. ABCG2/ABCB1 ratios in surgically resected tumor tissue (1.4 ± 0.2) were comparable to previously reported ABCG2/ABCB1 ratios in isolated human micro-vessels (1.3), which suggested that no overexpression of ABCB1 or ABCG2 occurred in the investigated tumors.

Conclusions: Our data suggest that the investigated brain tumors had an intact BBTB, which is impermeable to anticancer drugs, which are dual ABCB1/ABCG2 substrates. Therefore, effective drugs for antitumor treatment should have high passive permeability and lack ABCB1/ABCG2 substrate affinity.

Trial Registration: European Union Drug Regulating Authorities Clinical Trials Database (EUDRACT), 2011-004189-13. Registered on 23 February 2012, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2011-004189-13.
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http://dx.doi.org/10.1186/s13550-019-0581-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908538PMC
December 2019

Imaging P-Glycoprotein Induction at the Blood-Brain Barrier of a β-Amyloidosis Mouse Model with C-Metoclopramide PET.

J Nucl Med 2020 07 5;61(7):1050-1057. Epub 2019 Dec 5.

Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria

P-glycoprotein (ABC subfamily B member 1, ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting clearance of neurotoxic β-amyloid (Aβ) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease patients. Treatment with drugs that induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aβ deposits in the brain by enhancing clearance of Aβ peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer C-metoclopramide can measure ABCB1 induction at the BBB in a β-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Groups of wild-type and APP/PS1-21 mice aged 50 or 170 d underwent C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 d. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aβ levels. In separate groups of mice, radiolabeled metabolites of C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain () was calculated. PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aβ levels. There was a significant positive correlation between and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in was found. Metabolite analysis showed that most radioactivity in the brain comprised unmetabolized C-metoclopramide in all animal groups. C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in Alzheimer disease patients to noninvasively evaluate strategies to enhance the clearance properties of the BBB.
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http://dx.doi.org/10.2967/jnumed.119.237198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383073PMC
July 2020

Measurement of Hepatic ABCB1 and ABCG2 Transport Activity with [C]Tariquidar and PET in Humans and Mice.

Mol Pharm 2020 01 17;17(1):316-326. Epub 2019 Dec 17.

Department of Clinical Pharmacology , Medical University of Vienna , Vienna 1090 , Austria.

P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in the canalicular membrane of hepatocytes mediate the biliary excretion of drugs and drug metabolites. To measure hepatic ABCB1 and ABCG2 activity, we performed positron emission tomography (PET) scans with the ABCB1/ABCG2 substrate [C]tariquidar in healthy volunteers and wild-type, , , and mice without and with coadministration of unlabeled tariquidar. PET data were analyzed with a three-compartment pharmacokinetic model. [C]Tariquidar underwent hepatobiliary excretion in both humans and mice, and tariquidar coadministration caused a significant reduction in the rate constant for the transfer of radioactivity from the liver into bile (by -74% in humans and by -62% in wild-type mice), suggesting inhibition of canalicular efflux transporter activity. Radio-thin-layer chromatography analysis revealed that the majority of radioactivity (>87%) in the mouse liver and bile was composed of unmetabolized [C]tariquidar. PET data in transporter knockout mice revealed that both ABCB1 and ABCG2 mediated biliary excretion of [C]tariquidar. experiments indicated that tariquidar is not a substrate of major hepatic basolateral uptake transporters (SLCO1B1, SLCO1B3, SLCO2B1, SLC22A1, and SLC22A3). Our data suggest that [C]tariquidar can be used to measure hepatic canalicular ABCB1/ABCG2 transport activity without a confounding effect of uptake transporters.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b01060DOI Listing
January 2020

Pharmacokinetic Imaging with Radiolabeled Molecularly Targeted Anticancer Drugs.

J Nucl Med 2020 02 4;61(2):306. Epub 2019 Oct 4.

Medical University of Vienna Währinger-Gürtel 18-20 Vienna, Austria 1090 E-mail:

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http://dx.doi.org/10.2967/jnumed.119.236174DOI Listing
February 2020

Promise of Fully Integrated PET/MRI: Noninvasive Clinical Quantification of Cerebral Glucose Metabolism.

J Nucl Med 2020 02 2;61(2):276-284. Epub 2019 Aug 2.

QIMP Team, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.

We describe a fully automated processing pipeline to support the noninvasive absolute quantification of the cerebral metabolic rate for glucose (CMRGlc) in a clinical setting. This pipeline takes advantage of "anatometabolic" information associated with fully integrated PET/MRI. Ten healthy volunteers (5 men and /5 women; 27 ± 7 y old; 70 ± 10 kg) underwent a test-retest F-FDG PET/MRI examination of the brain. The imaging protocol consisted of a 60-min PET list-mode acquisition with parallel MRI acquisitions, including 3-dimensional time-of-flight MR angiography, MRI navigators, and a T1-weighted MRI scan. State-of-the-art MRI-based attenuation correction was derived from T1-weighted MRI (pseudo-CT [pCT]). For validation purposes, a low-dose CT scan was also performed. Arterial blood samples were collected as the reference standard (arterial input function [AIF]). The developed pipeline allows the derivation of an image-derived input function (IDIF), which is subsequently used to create CMRGlc maps by means of a Patlak analysis. The pipeline also includes motion correction using the MRI navigator sequence as well as a novel partial-volume correction that accounts for background heterogeneity. Finally, CMRGlc maps are used to generate a normative database to facilitate the detection of metabolic abnormalities in future patient scans. To assess the performance of the developed pipeline, IDIFs extracted by both CT-based attenuation correction (CT-IDIF) and MRI-based attenuation correction (pCT-IDIF) were compared with the reference standard (AIF) using the absolute percentage difference between the areas under the curves as well as the absolute percentage difference in regional CMRGlc values. The absolute percentage differences between the areas under the curves for CT-IDIF and pCT-IDIF were determined to be 1.4% ± 1.0% and 3.4% ± 2.6%, respectively. The absolute percentage difference in regional CMRGlc values based on CT-IDIF and pCT-IDIF differed by less than 6% from the reference values obtained from the AIF. By taking advantage of the capabilities of fully integrated PET/MRI, we developed a fully automated computational pipeline that allows the noninvasive determination of regional CMRGlc values in a clinical setting. This methodology might facilitate the proliferation of fully quantitative imaging into the clinical arena and, as a result, might contribute to improved diagnostic efficacy.
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http://dx.doi.org/10.2967/jnumed.119.229567DOI Listing
February 2020

Prevalence of Skin-specific Autoantibodies in HIV-infected Patients and Uninfected Controls.

Acta Derm Venereol 2019 Oct;99(11):978-983

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

Various autoantibodies are detected more frequently in HIV-infected individuals than in HIV-negative controls; however, limited data exist regarding autoimmune blistering skin diseases. Using enzyme-linked immunoassay (ELISA) and indirect immunofluore-scence, no difference in the frequency and magnitude of autoantibodies against BP180, BP230, desmoglein 1 and 3 was found between 594 HIV-infected patients and 248 uninfected controls in this cross-sectional study (16.0% vs. 11.7%, respectively, for at least one positive ELISA, p = 0.11). Interestingly, reactive syphilis serology in both HIV-infected individuals and uninfected controls was associated with positive anti-BP180 ELISA results (adjusted odds ratio (OR) 2.14, 95% confidence interval (CI) 1.07-4.29, p = 0.03 and OR 4.70, CI 1.3-16.86; p = 0.0180). Our study shows a comparably low prevalence of cutaneous autoantibodies in both HIV-infected patients and uninfected controls lacking signs of autoimmune blistering skin disease. Positive BP180 ELISA in the absence of clinical signs of bullous pemphigoid should prompt further evaluation for syphilis antibodies.
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http://dx.doi.org/10.2340/00015555-3251DOI Listing
October 2019

Long-lived particles at the energy frontier: the MATHUSLA physics case.

Rep Prog Phys 2019 Nov 11;82(11):116201. Epub 2019 Jun 11.

Department of Physics, University of Toronto, Toronto, ON M5S 1A7, Canada.

We examine the theoretical motivations for long-lived particle (LLP) signals at the LHC in a comprehensive survey of standard model (SM) extensions. LLPs are a common prediction of a wide range of theories that address unsolved fundamental mysteries such as naturalness, dark matter, baryogenesis and neutrino masses, and represent a natural and generic possibility for physics beyond the SM (BSM). In most cases the LLP lifetime can be treated as a free parameter from the [Formula: see text]m scale up to the Big Bang Nucleosynthesis limit of [Formula: see text] m. Neutral LLPs with lifetimes above [Formula: see text]100 m are particularly difficult to probe, as the sensitivity of the LHC main detectors is limited by challenging backgrounds, triggers, and small acceptances. MATHUSLA is a proposal for a minimally instrumented, large-volume surface detector near ATLAS or CMS. It would search for neutral LLPs produced in HL-LHC collisions by reconstructing displaced vertices (DVs) in a low-background environment, extending the sensitivity of the main detectors by orders of magnitude in the long-lifetime regime. We study the LLP physics opportunities afforded by a MATHUSLA-like detector at the HL-LHC, assuming backgrounds can be rejected as expected. We develop a model-independent approach to describe the sensitivity of MATHUSLA to BSM LLP signals, and compare it to DV and missing energy searches at ATLAS or CMS. We then explore the BSM motivations for LLPs in considerable detail, presenting a large number of new sensitivity studies. While our discussion is especially oriented towards the long-lifetime regime at MATHUSLA, this survey underlines the importance of a varied LLP search program at the LHC in general. By synthesizing these results into a general discussion of the top-down and bottom-up motivations for LLP searches, it is our aim to demonstrate the exceptional strength and breadth of the physics case for the construction of the MATHUSLA detector.
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http://dx.doi.org/10.1088/1361-6633/ab28d6DOI Listing
November 2019

Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography.

AAPS J 2019 04 29;21(4):61. Epub 2019 Apr 29.

Department of Clinical Pharmacology, Medical University of Vienna, A-1090, Vienna, Austria.

Positron emission tomography (PET) imaging with radiolabeled drugs holds great promise to assess the influence of membrane transporters on hepatobiliary clearance of drugs. To exploit the full potential of PET, quantitative pharmacokinetic models are required. In this study, we evaluated the suitability of different compartment models to describe the hepatic disposition of [C]erlotinib as a small-molecule model drug which undergoes transporter-mediated hepatobiliary excretion. We analyzed two different, previously published data sets in healthy volunteers, in which a baseline [C]erlotinib PET scan was followed by a second PET scan either after oral intake of unlabeled erlotinib (300 mg) or after intravenous infusion of the prototypical organic anion-transporting polypeptide inhibitor rifampicin (600 mg). We assessed a three-compartment (3C) and a four-compartment (4C) model, in which either a sampled arterial blood input function or a mathematically derived dual input function (DIF), which takes the contribution of the portal vein to the liver blood supply into account, was used. Both models provided acceptable fits of the observed PET data in the liver and extrahepatic bile duct and gall bladder. Changes in model outcome parameters between scans were consistent with the involvement of basolateral hepatocyte uptake and canalicular efflux transporters in the hepatobiliary clearance of [C]erlotinib. Our results demonstrated that inclusion of a DIF did not lead to substantial improvements in model fits. The models developed in this work represent a step forward in applying PET as a tool to assess the impact of hepatic transporters on drug disposition and their involvement in drug-drug interactions.
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http://dx.doi.org/10.1208/s12248-019-0323-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488550PMC
April 2019

Imaging P-Glycoprotein Function at the Blood-Brain Barrier as a Determinant of the Variability in Response to Central Nervous System Drugs.

Clin Pharmacol Ther 2019 05 23;105(5):1061-1064. Epub 2019 Mar 23.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1002/cpt.1402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491962PMC
May 2019

Inhibition of ABCB1 and ABCG2 at the Mouse Blood-Brain Barrier with Marketed Drugs To Improve Brain Delivery of the Model ABCB1/ABCG2 Substrate [C]erlotinib.

Mol Pharm 2019 03 11;16(3):1282-1293. Epub 2019 Feb 11.

Center for Health & Bioresources , AIT Austrian Institute of Technology GmbH , 2444 Seibersdorf , Austria.

P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters at the blood-brain barrier (BBB), which effectively restrict brain distribution of diverse drugs, such as tyrosine kinase inhibitors. There is a crucial need for pharmacological ABCB1 and ABCG2 inhibition protocols for a more effective treatment of brain diseases. In the present study, seven marketed drugs (osimertinib, erlotinib, nilotinib, imatinib, lapatinib, pazopanib, and cyclosporine A) and one nonmarketed drug (tariquidar), with known in vitro ABCB1/ABCG2 inhibitory properties, were screened for their inhibitory potency at the BBB in vivo. Positron emission tomography (PET) using the model ABCB1/ABCG2 substrate [C]erlotinib was performed in mice. Tested inhibitors were administered as i.v. bolus injections at 30 min before the start of the PET scan, followed by a continuous i.v. infusion for the duration of the PET scan. Five of the tested drugs increased total distribution volume of [C]erlotinib in the brain ( V) compared to vehicle-treated animals (tariquidar, + 69%; erlotinib, + 19% and +23% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 22%; lapatinib, + 25%; and cyclosporine A, + 49%). For all drugs, increases in [C]erlotinib brain distribution were lower than in Abcb1a/bAbcg2 mice (+149%), which suggested that only partial ABCB1/ABCG2 inhibition was reached at the mouse BBB. The plasma concentrations of the tested drugs at the time of the PET scan were higher than clinically achievable plasma concentrations. Some of the tested drugs led to significant increases in blood radioactivity concentrations measured at the end of the PET scan (erlotinib, + 103% and +113% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 125%; and cyclosporine A, + 101%), which was most likely caused by decreased hepatobiliary excretion of radioactivity. Taken together, our data suggest that some marketed tyrosine kinase inhibitors may be repurposed to inhibit ABCB1 and ABCG2 at the BBB. From a clinical perspective, moderate increases in brain delivery despite the administration of high i.v. doses as well as peripheral drug-drug interactions due to transporter inhibition in clearance organs question the translatability of this concept.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b01217DOI Listing
March 2019

Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-Study.

BMC Cardiovasc Disord 2019 01 24;19(1):26. Epub 2019 Jan 24.

Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany.

Background: The aim of our study was the identification of genetic variants associated with postoperative complications after cardiac surgery.

Methods: We conducted a prospective, double-blind, multicenter, randomized trial (RIPHeart). We performed a genome-wide association study (GWAS) in 1170 patients of both genders (871 males, 299 females) from the RIPHeart-Study cohort. Patients undergoing non-emergent cardiac surgery were included. Primary endpoint comprises a binary composite complication rate covering atrial fibrillation, delirium, non-fatal myocardial infarction, acute renal failure and/or any new stroke until hospital discharge with a maximum of fourteen days after surgery.

Results: A total of 547,644 genotyped markers were available for analysis. Following quality control and adjustment for clinical covariate, one SNP reached genome-wide significance (PHLPP2, rs78064607, p = 3.77 × 10) and 139 (adjusted for all other outcomes) SNPs showed promising association with p < 1 × 10 from the GWAS.

Conclusions: We identified several potential loci, in particular PHLPP2, BBS9, RyR2, DUSP4 and HSPA8, associated with new-onset of atrial fibrillation, delirium, myocardial infarction, acute kidney injury and stroke after cardiac surgery.

Trial Registration: The study was registered with ClinicalTrials.gov NCT01067703, prospectively registered on 11 Feb 2010.
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http://dx.doi.org/10.1186/s12872-019-1002-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345037PMC
January 2019

Does airborne ultrasound lead to activation of the auditory cortex?

Biomed Tech (Berl) 2019 Aug;64(4):481-493

Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Bundesallee 100, Braunschweig 38116, Germany.

As airborne ultrasound can be found in many technical applications and everyday situations, the question as to whether sounds at these frequencies can be heard by human beings or whether they present a risk to their hearing system is of great practical relevance. To objectively study these issues, the monaural hearing threshold in the frequency range from 14 to 24 kHz was determined for 26 test subjects between 19 and 33 years of age using pure tone audiometry. The hearing threshold values increased strongly with increasing frequency up to around 21 kHz, followed by a range with a smaller slope toward 24 kHz. The number of subjects who could respond positively to the threshold measurements decreased dramatically above 21 kHz. Brain activation was then measured by means of magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) and with acoustic stimuli at the same frequencies, with sound pressure levels (SPLs) above and below the individual threshold. No auditory cortex activation was found for levels below the threshold. Although test subjects reported audible sounds above the threshold, no brain activity was identified in the above-threshold case under current experimental conditions except at the highest sensation level, which was presented at the lowest test frequency.
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http://dx.doi.org/10.1515/bmt-2018-0048DOI Listing
August 2019

Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate C-Metoclopramide Assessed with PET Imaging in Humans.

J Nucl Med 2019 07 10;60(7):985-991. Epub 2019 Jan 10.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

PET with avid substrates of P-glycoprotein (ABCB1) provided evidence of the role of this efflux transporter in effectively restricting the brain penetration of its substrates across the human blood-brain barrier (BBB). This may not reflect the situation for weak ABCB1 substrates including several antidepressants, antiepileptic drugs, and neuroleptics, which exert central nervous system effects despite being transported by ABCB1. We performed PET with the weak ABCB1 substrate C-metoclopramide in humans to elucidate the impact of ABCB1 function on its brain kinetics. Ten healthy male subjects underwent 2 consecutive C-metoclopramide PET scans without and with ABCB1 inhibition using cyclosporine A (CsA). Pharmacokinetic modeling was performed to estimate the total volume of distribution () and the influx () and efflux () rate constants between plasma and selected brain regions. Furthermore, C-metoclopramide washout from the brain was estimated by determining the elimination slope () of the brain time-activity curves. In baseline scans, C-metoclopramide showed appreciable brain distribution ( = 2.11 ± 0.33 mL/cm). During CsA infusion, whole-brain gray matter and were increased by 29% ± 17% and 9% ± 12%, respectively. was decreased by 15% ± 5%, consistent with a decrease in (-32% ± 18%). The impact of CsA on outcome parameters was significant and similar across brain regions except for the pituitary gland, which is not protected by the BBB. Our results show for the first time that ABCB1 does not solely account for the "barrier" property of the BBB but also acts as a detoxifying system to limit the overall brain exposure to its substrates at the human blood-brain interface.
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http://dx.doi.org/10.2967/jnumed.118.219972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604692PMC
July 2019

Paths of femoral nerve catheters placed using ultrasound-guided in plane vs out of plane techniques: A randomized controlled clinical trial.

Medicine (Baltimore) 2018 Oct;97(43):e12958

Department of Anesthesiology, Emergency and Intensive Care Medicine, University Medical Center, University of Goettingen, Goettingen.

Background: Continuous blockade of the femoral nerve is widely used for postoperative analgesia after hip surgery. It can be achieved by ultrasound-guided placement of a femoral nerve catheter via either the in plane (IP) or out of plane (OOP) technique. On the basis of postoperative radiographs, we evaluated the paths of femoral nerve catheters with respect to both techniques and its effect on postoperative analgesia.

Methods: Thirty-four patients were randomized to receive a radiopaque femoral nerve catheter via either the IP or OOP technique. The paths and tip position of the catheters were evaluated in postoperative frontal radiographs of the operated hip joint concerning a predefined target region and four neighboring regions. Pain scores were assessed using a numeric rating scale (0-10).

Results: Sixteen IP patients and 18 OOP patients were included in the study. The catheter path was radiographically evaluated in 13 IP patients and in 10 OOP patients. The catheter tips were located within the target region in 39% of the IP group and in 50% of the OOP group. The catheter tip was 0.00 cm [-3.80 to 3.84] and -1.19 cm [-12.27 to 0.00] (median [range]) from the target region in the OOP group and IP group, respectively (P = .045). Catheters flipped distally more often in the IP group (IP: 61.5%, OOP: 10.0%; P = .01). There were no marked differences in the pain scores of either group.

Conclusion: Femoral nerve catheters inserted by the ultrasound-guided IP technique flip distally more frequently than catheters inserted by the OOP technique. Moreover, the distance between the catheter tip and the trunk of the femoral nerve is greater for IP catheters than for OOP catheters. Despite these findings, postoperative analgesia did not seem to differ between the 2 techniques.
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http://dx.doi.org/10.1097/MD.0000000000012958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221616PMC
October 2018

Age dependency of cerebral P-glycoprotein function in wild-type and APPPS1 mice measured with PET.

J Cereb Blood Flow Metab 2020 01 24;40(1):150-162. Epub 2018 Oct 24.

Center for Health & Bioresources, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.

P-glycoprotein (P-gp, ABCB1) is an efflux transporter at the blood-brain barrier (BBB), which mediates clearance of beta-amyloid (Aβ) from brain into blood. We used ()-[C]verapamil PET in combination with partial P-gp inhibition with tariquidar to measure cerebral P-gp function in a beta-amyloidosis mouse model (APPtg) and in control mice at three different ages (50, 200 and 380 days). Following tariquidar pre-treatment (4 mg/kg), whole brain-to-plasma radioactivity concentration ratios () were significantly higher in APPtg than in wild-type mice aged 50 days, pointing to decreased cerebral P-gp function. Moreover, we found an age-dependent decrease in cerebral P-gp function in both wild-type and APPtg mice of up to -50%. Alterations in P-gp function were more pronounced in Aβ-rich brain regions (hippocampus, cortex) than in a control region with negligible Aβ load (cerebellum). PET results were confirmed by immunohistochemical staining of P-gp in brain microvessels. Our results confirm previous findings of reduced P-gp function in Alzheimer's disease mouse models and show that our PET protocol possesses adequate sensitivity to measure these functional changes in vivo. Our PET protocol may find use in clinical studies to test the efficacy of drugs to induce P-gp function at the human BBB to enhance Aβ clearance.
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http://dx.doi.org/10.1177/0271678X18806640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928546PMC
January 2020

A Proof-of-Concept Study to Inhibit ABCG2- and ABCB1-Mediated Efflux Transport at the Human Blood-Brain Barrier.

J Nucl Med 2019 04 20;60(4):486-491. Epub 2018 Sep 20.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

The adenosine triphosphate-binding cassette transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are 2 efflux transporters at the blood-brain barrier (BBB) that effectively restrict brain distribution of dual ABCB1/ABCG2 substrate drugs, such as tyrosine kinase inhibitors. Pharmacologic inhibition of ABCB1/ABCG2 may improve the efficacy of dual-substrate drugs for treatment of brain tumors, but no marketed ABCB1/ABCG2 inhibitors are currently available. In the present study, we examined the potential of supratherapeutic-dose oral erlotinib to inhibit ABCB1/ABCG2 activity at the human BBB. : Healthy men underwent 2 consecutive PET scans with C-erlotinib: a baseline scan and a second scan either with concurrent intravenous infusion of the ABCB1 inhibitor tariquidar (3.75 mg/min, = 5) or after oral intake of single ascending doses of erlotinib (300 mg, = 7; 650 mg, = 8; or 1,000 mg, = 2). : Although tariquidar administration had no effect on C-erlotinib brain distribution, oral erlotinib led, at the 650-mg dose, to significant increases in volume of distribution (23% ± 13%, = 0.008), influx rate constant of radioactivity from plasma into brain (58% ± 26%, = 0.008), and area under the brain time-activity curve (78% ± 17%, = 0.008), presumably because of combined partial saturation of ABCG2 and ABCB1 activity. Inclusion of further subjects into the 1,000-mg dose group was precluded by adverse skin events (rash). : Supratherapeutic-dose erlotinib may be used to enhance brain delivery of ABCB1/ABCG2 substrate anticancer drugs, but its clinical applicability for continuous ABCB1/ABCG2 inhibition at the BBB may be limited by safety concerns.
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http://dx.doi.org/10.2967/jnumed.118.216432DOI Listing
April 2019

Effect of Rifampicin on the Distribution of [C]Erlotinib to the Liver, a Translational PET Study in Humans and in Mice.

Mol Pharm 2018 10 14;15(10):4589-4598. Epub 2018 Sep 14.

Center for Health & Bioresources , AIT Austrian Institute of Technology GmbH , 2444 Seibersdorf , Austria.

Organic anion-transporting polypeptides (OATPs) mediate the uptake of various drugs from blood into the liver in the basolateral membrane of hepatocytes. Positron emission tomography (PET) is a potentially powerful tool to assess the activity of hepatic OATPs in vivo, but its utility critically depends on the availability of transporter-selective probe substrates. We have shown before that among the three OATPs expressed in hepatocytes (OATP1B1, OATP1B3, and OATP2B1), [C]erlotinib is selectively transported by OATP2B1. In contrast to OATP1B1 and OATP1B3, OATP2B1 has not been thoroughly explored yet, and no specific probe substrates are currently available. To assess if the prototypical OATP inhibitor rifampicin can inhibit liver uptake of [C]erlotinib in vivo, we performed [C]erlotinib PET scans in six healthy volunteers without and with intravenous pretreatment with rifampicin (600 mg). In addition, FVB mice underwent [C]erlotinib PET scans without and with concurrent intravenous infusion of high-dose rifampicin (100 mg/kg). Rifampicin caused a moderate reduction in the liver distribution of [C]erlotinib in humans, while a more pronounced effect of rifampicin was observed in mice, in which rifampicin plasma concentrations were higher than in humans. In vitro uptake experiments in an OATP2B1-overexpressing cell line indicated that rifampicin inhibited OATP2B1 transport of [C]erlotinib in a concentration-dependent manner with a half-maximum inhibitory concentration of 72.0 ± 1.4 μM. Our results suggest that rifampicin-inhibitable uptake transporter(s) contributed to the liver distribution of [C]erlotinib in humans and mice and that [C]erlotinib PET in combination with rifampicin may be used to measure the activity of this/these uptake transporter(s) in vivo. Furthermore, our data suggest that a standard clinical dose of rifampicin may exert in vivo a moderate inhibitory effect on hepatic OATP2B1.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00588DOI Listing
October 2018

Impact of rifampicin-inhibitable transport on the liver distribution and tissue kinetics of erlotinib assessed with PET imaging in rats.

EJNMMI Res 2018 Aug 16;8(1):81. Epub 2018 Aug 16.

Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, F-91400, Orsay, France.

Background: Erlotinib is an epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor approved for treatment of non-small cell lung cancer. The wide inter-individual pharmacokinetic (PK) variability of erlotinib may impact treatment outcome and/or toxicity. Recent in vivo studies reported a nonlinear uptake transport of erlotinib into the liver, suggesting carrier-mediated system(s) to mediate its hepatobiliary clearance. Erlotinib has been identified in vitro as a substrate of organic anion-transporting polypeptide (OATP) transporters which expression does not restrict to hepatocytes and may impact the tissue uptake of erlotinib in vivo.

Results: The impact of rifampicin (40 mg/kg), a potent OATP inhibitor, on the liver uptake and exposure to tissues of C-erlotinib was investigated in rats (4 animals per group) using positron emission tomography (PET) imaging. Tissue pharmacokinetics (PK) and corresponding exposure (area under the curve, AUC) were assessed in the liver, kidney cortex, abdominal aorta (blood pool) and the lungs. The plasma PK of parent C-erlotinib was also measured using arterial blood sampling to estimate the transfer rate constant (k) of C-erlotinib from plasma into different tissues. PET images unveiled the predominant distribution of C-erlotinib-associated radioactivity to the liver, which gradually moved to the intestine, thus highlighting hepatobiliary clearance. C-erlotinib also accumulated in the kidney cortex. Rifampicin did not impact AUC but reduced k (p < 0.001), causing a significant 27.3% decrease in liver exposure (p < 0.001). Moreover, a significant decrease in k with a concomitant decrease in AUC (- 30.4%, p < 0.001) were observed. Rifampicin neither affected k nor AUC.

Conclusions: Our results suggest that C-erlotinib is an in vivo substrate of rOATP transporters expressed in the liver and possibly of rifampicin-inhibitable transporter(s) in the kidneys. Decreased C-erlotinib uptake by elimination organs did not translate into changes in systemic exposure and exposure to the lungs, which are a target tissue for erlotinib therapy.
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http://dx.doi.org/10.1186/s13550-018-0434-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095934PMC
August 2018

Higgs Pair Production as a Signal of Enhanced Yukawa Couplings.

Phys Rev Lett 2018 Jul;121(2):021801

PRISMA Cluster of Excellence & Mainz Institute for Theoretical Physics, Johannes Gutenberg University, 55099 Mainz, Germany.

We present a nontrivial correlation between the enhancement of the Higgs-fermion couplings and the Higgs pair production cross section in two Higgs doublet models with a flavor symmetry, with implications for LHC searches. This symmetry suppresses flavor-changing neutral couplings of the Higgs boson and allows for a partial explanation of the hierarchy in the Yukawa sector. After taking into account the constraints from electroweak precision measurements, Higgs coupling strength measurements, and unitarity and perturbativity bounds, we identify an interesting region of parameter space leading to enhanced Yukawa couplings as well as enhanced di-Higgs gluon fusion production at the LHC reach. This effect is visible in both the resonant and nonresonant contributions to the Higgs pair production cross section. We encourage dedicated searches based on differential distributions as a novel way to indirectly probe enhanced Higgs couplings to light fermions.
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http://dx.doi.org/10.1103/PhysRevLett.121.021801DOI Listing
July 2018

P-Glycoprotein (ABCB1) Inhibits the Influx and Increases the Efflux of C-Metoclopramide Across the Blood-Brain Barrier: A PET Study on Nonhuman Primates.

J Nucl Med 2018 10 10;59(10):1609-1615. Epub 2018 May 10.

UMR 1023 IMIV, Service Hospitalier Frédéric Joliot, CEA, INSERM, Université Paris Sud, CNRS, Université Paris-Saclay, Orsay, France

PET imaging using radiolabeled avid substrates of the ATP-binding cassette (ABC) transporter P-glycoprotein (ABCB1) has convincingly revealed the role of this major efflux transporter in limiting the influx of its substrates from blood into the brain across the blood-brain barrier (BBB). Many drugs, such as metoclopramide, are weak ABCB1 substrates and distribute into the brain even when ABCB1 is fully functional. In this study, we used kinetic modeling and validated simplified methods to highlight and quantify the impact of ABCB1 on the BBB influx and efflux of C-metoclopramide, as a model of a weak ABCB1 substrate, in nonhuman primates. The regional brain kinetics of a tracer dose of C-metoclopramide (298 ± 44 MBq) were assessed in baboons using PET without ( = 4) or with ( = 4) intravenous coinfusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution (), as well as the influx () and efflux () rate constants, using a 1-tissue-compartment model. Modeling outcome parameters were correlated with image-derived parameters, that is, areas under the regional time-activity curves (AUCs) from 0 to 30 min and from 30 to 60 min (SUV⋅min) and the elimination slope (; min) from 30 to 60 min. Tariquidar significantly increased the brain distribution of C-metoclopramide ( = 4.3 ± 0.5 mL/cm and 8.7 ± 0.5 mL/cm for baseline and ABCB1 inhibition conditions, respectively, < 0.001), with a 1.28-fold increase in ( < 0.05) and a 1.64-fold decrease in ( < 0.001). The effect of tariquidar was homogeneous across different brain regions. The parameters most sensitive to ABCB1 inhibition were (2.02-fold increase) and AUC from 30 to 60 min (2.02-fold increase). correlated significantly ( < 0.0001) with AUC from 30 to 60 min ( = 0.95), with AUC from 0 to 30 min ( = 0.87), and with ( = 0.62). C-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function.
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http://dx.doi.org/10.2967/jnumed.118.210104DOI Listing
October 2018

Pathways to use of communication campaigns' evaluation findings within international organizations.

Eval Program Plann 2018 08 1;69:82-91. Epub 2018 May 1.

Social Psychology and Research Methodology, London School of Economics and Political Science, London, UK. Electronic address:

This article presents a study on the pathways and processes regarding the use of evaluation findings of communication campaigns from two international organizations, the Office of the High Commissioner for Human Rights (OHCHR) and the International Committee of the Red Cross (ICRC). Several years after the completion of the campaigns and their evaluations, our research identified 28 instances of use and six instances of non-use of the evaluation results, of which the large majority being surprising in nature. Results showed that evaluation use facilitated formal and informal changes at the individual and the organizational level; and, this pattern occurred in a predominantly non-linear fashion, interconnected and overlapping, while gradually decreasing in time and space. Evaluation use was mostly unpredictable, which reflected how meanings are constructed by staff members, as they adjusted and interpreted the findings in opportunistic ways.
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http://dx.doi.org/10.1016/j.evalprogplan.2018.04.013DOI Listing
August 2018

Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration.

Eur J Drug Metab Pharmacokinet 2018 Oct;43(5):599-606

Department of Internal Medicine I, Clinical Division of Infectious Diseases and Tropical Medicine, Medical University Vienna, Vienna, Austria.

Background And Objective: P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood-brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of tariquidar in rats after single intravenous, oral, and intraperitoneal administration.

Methods: Two different tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice.

Results: In contrast to human data, the present study found a high bioavailability of tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B.

Conclusion: The present findings extend the available information on tariquidar and provide a basis for future studies involving oral administration of this compound.
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http://dx.doi.org/10.1007/s13318-018-0474-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133083PMC
October 2018