Publications by authors named "Julian Maier"

13 Publications

  • Page 1 of 1

α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and uptake1 and uptake2 monoamine transporters.

Neuropharmacology 2021 Apr 20;190:108570. Epub 2021 Apr 20.

Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria; AddRess Centre for Addiction Research and Science, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria. Electronic address:

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108570DOI Listing
April 2021

Meclofenamate causes loss of cellular tethering and decoupling of functional networks in glioblastoma.

Neuro Oncol 2021 Apr 17. Epub 2021 Apr 17.

Translational NeuroOncology Research Group, Medical Center University of Freiburg, Germany.

Background: Glioblastoma cells assemble to a syncytial communicating network based on tumor microtubes (TMs) as ultra-long membrane protrusions. The relationship between network architecture and transcriptional profile remains poorly investigated. Drugs that interfere within this syncytial connectivity such as meclofenamate (MFA) may be highly attractive for glioblastoma therapy.

Methods: In a human neocortical slice model using glioblastoma cell populations of different transcriptional signatures, three-dimensional tumor networks were reconstructed and TM-based intercellular connectivity was mapped on the base of two-photon imaging data. MFA was used to modulate morphological and functional connectivity; downstream effects of MFA treatment were investigated by RNA sequencing and fluorescence-activated cell sorting (FACS) analysis.

Results: TM-based network morphology strongly differed between the transcriptional cellular subtypes of glioblastoma and was dependent on axon guidance molecule expression. MFA revealed both a functional and morphological demolishment of glioblastoma network architectures which was reflected by a reduction of TM-mediated intercellular cytosolic traffic as well as a breakdown of TM length. RNA sequencing confirmed a downregulation of NCAM and axon guidance molecule signaling upon MFA treatment. Loss of glioblastoma communicating networks was accompanied by a failure in the upregulation of genes that are required for DNA repair in response to TMZ-treatment and culminated in profound treatment response to TMZ-mediated toxicity.

Conclusion: The capacity of TM formation reflects transcriptional cellular heterogeneity. MFA effectively demolishes functional and morphological TM-based syncytial network architectures. These findings might pave the way to a clinical implementation of MFA as a TM-targeted therapeutic approach.
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http://dx.doi.org/10.1093/neuonc/noab092DOI Listing
April 2021

Bacterial but no SARS-CoV-2 contamination after terminal disinfection of tertiary care intensive care units treating COVID-19 patients.

Antimicrob Resist Infect Control 2021 01 12;10(1):11. Epub 2021 Jan 12.

Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland.

Background: In intensive care units (ICUs) treating patients with Coronavirus disease 2019 (COVID-19) invasive ventilation poses a high risk for aerosol and droplet formation. Surface contamination of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) or bacteria can result in nosocomial transmission.

Methods: Two tertiary care COVID-19 intensive care units treating 53 patients for 870 patient days were sampled after terminal cleaning and preparation for regular use to treat non-COVID-19 patients.

Results: A total of 176 swabs were sampled of defined locations covering both ICUs. No SARS-CoV-2 ribonucleic acid (RNA) was detected. Gram-negative bacterial contamination was mainly linked to sinks and siphons. Skin flora was isolated from most swabbed areas and Enterococcus faecium was detected on two keyboards.

Conclusions: After basic cleaning with standard disinfection measures no remaining SARS-CoV-2 RNA was detected. Bacterial contamination was low and mainly localised in sinks and siphons.
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http://dx.doi.org/10.1186/s13756-021-00885-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802978PMC
January 2021

Efficacy and safety of tafenoquine for malaria chemoprophylaxis (1998-2020): A systematic review and meta-analysis.

Travel Med Infect Dis 2021 Jan-Feb;39:101908. Epub 2020 Nov 20.

University of Zurich Centre for Travel Medicine, WHO Collaborating Centre for Travellers' Health, Department of Public and Global Health, MilMedBiol Competence Centre, Institute for Epidemiology, Biostatistics and Prevention, University of Zurich, Hirschengraben 84, 8001, Zurich, Switzerland. Electronic address:

Background: In 2018, tafenoquine was approved for malaria chemoprophylaxis. We evaluated all available data on the safety and efficacy of tafenoquine chemoprophylaxis.

Methods: This systematic review followed the PRISMA guidelines and was registered on PROSPERO (CRD42019123839). We searched PubMed, Embase, Scopus, CINAHL and Cochrane databases. Two authors (JDM, PS) screened all papers.

Results: We included 44 papers in the qualitative and 9 in the quantitative analyses. These 9 randomized, controlled trials included 2495 participants, aged 12-60 years with 27.3% women. Six studies were conducted in Plasmodium spp.-endemic regions; two were human infection studies. 200 mg weekly tafenoquine and higher dosages lead to a significant reduction of Plasmodium spp. infection compared to placebo and were comparable to 250 mg mefloquine weekly with a protective efficacy between 77.9 and 100% or a total risk ratio of 0.22 (95%-CI: 0.07-0.73; p = 0.013) in favour of tafenoquine. Adverse events (AE) were comparable in frequency and severity between tafenoquine and comparator arms. One study reported significantly more gastrointestinal events in tafenoquine users (p ≤ 0.001). Evidence of increased, reversible, asymptomatic vortex keratopathy in subjects with prolonged tafenoquine exposures was found. A single, serious event of decreased macular sensitivity occurred.

Conclusion: This systematic review and meta-analysis of trials of G6PD-normal adults show that weekly tafenoquine 200 mg is well tolerated and effective as malaria chemoprophylaxis focusing primarily on Plasmodium falciparum but also on Plasmodium vivax. Our safety analysis is limited by heterogenous methods of adverse events reporting. Further research is indicated on the use of tafenoquine in diverse traveller populations.
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http://dx.doi.org/10.1016/j.tmaid.2020.101908DOI Listing
November 2020

Cardiac Computed Tomography-Derived Left Atrial Volume Index as a Predictor of Long-Term Success of Cryo-Ablation in Patients With Atrial Fibrillation.

Am J Cardiol 2021 02 2;140:69-77. Epub 2020 Nov 2.

Department of Cardiology, Kepler University Hospital, Medical Faculty, Johannes Kepler University Linz, Linz, Austria.

Patients with symptomatic, drug-refractory atrial fibrillation (AF) are frequently treated with catheter ablation. Cryo-ablation has been established as an alternative to radiofrequency ablation but long-term outcome data are still limited. This study aimed at elucidating the influence of the left atrial volume index (LAVI), derived from cardiac computed tomography (cCT) data, on the long-term outcome of ablation-naïve AF patients, after their first cryo-ablation. 415 patients (n = 290 [69.90%] male, 60.00 [IQR: 53.00 to 68.00] years old) who underwent a cCT and subsequent cryo-ablation index procedure were included in this single centre retrospective data analysis. A composite end point was defined (AF on electrocardiogram and/or electric cardioversion and/or re-do). Patients were closely followed for a year and then contacted for long-term follow-up after a median of 53.00 months (IQR: 34.50 to 73.00). Statistical analyses of the outcome and predictors of AF recurrence were conducted. In 224 patients (53.98%) no evidence of AF recurrence could be found. LAVI differed significantly between the positive and adverse (AF recurrence) outcome group (49.96 vs 56.07 ml/m, p < 0.001). Cox regression analyses revealed cCT LAVI (HR: 1.022, 95% CI: 1.013 to 1.031, p < 0.001), BMI (HR: 1.044, 95% CI: 1.005 to 1.084, p < 0.05) and the type of AF (HR: 1.838 for nonparoxysmal AF, 95% CI: 1.214 to 2.781, p < 0.01) to be effective predictors of AF recurrence. A prognostic cCT LAVI cut-off value of 51.99 ml/m was calculated and must be validated in future prospective studies. In conclusion, LAVI is an accurate, yet underutilized predictor of AF recurrence after pulmonary vein isolation with cryo-energy and scores for calculating AF recurrence or progression risks might underemphasize the importance of CT-derived LAVI as a predictive factor.
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http://dx.doi.org/10.1016/j.amjcard.2020.10.061DOI Listing
February 2021

Thrombolysis as first-line therapy for Medtronic/HeartWare HVAD left ventricular assist device thrombosis.

Eur J Cardiothorac Surg 2020 12;58(6):1182-1191

Department of Surgery, Division of Cardiac Surgery, Medical University of Vienna, Vienna, Austria.

Objectives: We reviewed our institutional experience with intravenous thrombolysis (TL) as first-line therapy in patients with Medtronic/HeartWare HVAD left ventricular assist device pump thrombosis (PT).

Methods: From March 2006 to November 2018, 30 Medtronic/HeartWare HVAD left ventricular assist device patients had 48 PT events. We analysed outcomes with intravenous Alteplase as a first-line therapy for PT. Pump exchange or urgent heart transplantation was only considered after the failure of TL or existing contraindications to TL.

Results: TL was used as the first-line therapy in 44 PT events in 28 patients without a contraindication to TL. TL was successful in 61.4% of PT events. More than 1 cycle of TL was necessary in 55.6% of events. The combined success of TL and heart transplantation or device exchange was 81.8%. In 15.9% of events, PT was fatal. Causes of death were severe complications (9.1%) related to TL or discontinuation of therapy for multi-organ failure (6.8%). Intracranial bleeding and arterial thromboembolism were observed in 4.5% and 11.5% of the PT events after TL.

Conclusions: Intravenous TL as a first-line therapy for PT in Medtronic/HeartWare HVAD patients can be a reasonable treatment option and does not preclude subsequent heart transplantation or device exchange. However, thromboembolic and bleeding complications are common. The decision to perform TL or device exchange should, therefore, be made on an individual basis after balancing the risks and benefits of different treatment approaches.
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http://dx.doi.org/10.1093/ejcts/ezaa180DOI Listing
December 2020

Repurposing antimalarials and other drugs for COVID-19.

Travel Med Infect Dis 2020 Mar - Apr;34:101658. Epub 2020 Apr 2.

Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, IHU-Méditerranée Infection, Marseille, France.

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http://dx.doi.org/10.1016/j.tmaid.2020.101658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194516PMC
May 2020

A critical examination of the main premises of Traditional Chinese Medicine.

Wien Klin Wochenschr 2020 May 20;132(9-10):260-273. Epub 2020 Mar 20.

Institute of Pharmacology, Medical University Vienna, Vienna, Austria.

Traditional Chinese Medicine (TCM) consists of a plethora of therapeutic approaches aiming to both characterize and treat diseases. Its utilization has gained significant popularity in the western world and is even backed by the World Health Organization's decision to include TCM diagnostic patterns into the new revision of the International Classification of Diseases code, the global standard for diagnostic health information. As these developments and potentially far-reaching decisions can affect modern healthcare systems and daily clinical work as well as wildlife conservation, its underlying factual basis must be critically examined. This article therefore provides an overview of the evidence underlying the basic TCM concepts, such as Qi, meridians, acupuncture, pulse and tongue diagnostics as well as traditional herbal treatments. Moreover, it discusses whether scientific literature on TCM reflects the current standard for evidence-based research, as described in good scientific practice and good clinical practice guidelines. Importantly, misinformation regarding the therapeutic efficacy of animal-derived substances has lead and currently leads to problems with wildlife preservation and animal ethics. Nevertheless, the (re-)discovery of artemisinin more than 50 years ago introduced a novel development in TCM: the commingling of Eastern and Western medicine, the appreciation of both systems. The need for more rigorous approaches, fulfilment of and agreement to current guidelines to achieve high-quality research are of utmost relevance. Thereby, ancient knowledge of herbal species and concoctions may serve as a possible treasure box rather than Pandora's box.
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http://dx.doi.org/10.1007/s00508-020-01625-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253514PMC
May 2020

Antiviral potential of 3'-sialyllactose- and 6'-sialyllactose-conjugated dendritic polymers against human and avian influenza viruses.

Sci Rep 2020 01 21;10(1):768. Epub 2020 Jan 21.

Institute of Medical Virology, University of Zurich, 8057, Zurich, Switzerland.

Current treatment options for influenza virus infections in humans are limited and therefore the development of novel antivirals is of high priority. Inhibiting influenza virus attachment to host cells would provide an early and efficient block of the infection and thus, receptor analogs have been considered as options for antiviral treatment. Here, we describe the rapid and efficient synthesis of PAMAM dendrimers conjugated with either 3'-sialyllactose (3SL) or 6'-sialyllactose (6SL) and their potential to inhibit a diverse range of human and avian influenza virus strains. We show in a hemagglutination inhibition (HAI) assay that human IAV strains can be inhibited by (6SL)- and to a lesser extent also by (3SL)-conjugated PAMAM dendrimers. In contrast, avian strains could only be inhibited by (3SL)-conjugated dendrimers. Importantly, the differential sensitivities of human and avian IAV to the two types of sialyllactose-conjugated dendrimers could be confirmed in cell-based neutralization assays. Based on our findings, we suggest to further develop both, (3SL)- and (6SL)-conjugated PAMAM dendrimers, as influenza virus inhibitors.
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http://dx.doi.org/10.1038/s41598-020-57608-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972948PMC
January 2020

Astrogliosis Releases Pro-Oncogenic Chitinase 3-Like 1 Causing MAPK Signaling in Glioblastoma.

Cancers (Basel) 2019 Sep 26;11(10). Epub 2019 Sep 26.

Translational NeuroOncology Research Group, Medical Center, University of Freiburg, 79106 Freiburg, Germany.

Although reactive astrocytes constitute a major component of the cellular environment in glioblastoma, their function and crosstalk to other components of the environment is still poorly understood. Gene expression analysis of purified astrocytes from both the tumor core and non-infiltrated cortex reveals a tumor-related up-regulation of Chitinase 3-like 1 (CHI3L1), a cytokine which is related to inflammation, extracellular tissue remodeling, and fibrosis. Further, we established and validated a co-culture model to investigate the impact of reactive astrocytes within the tumor microenvironment. Here we show that reactive astrocytes promote a subtype-shift of glioblastoma towards the mesenchymal phenotype, driving mitogen-activated protein kinases (MAPK) signaling as well as increased proliferation and migration. In addition, we demonstrate that MAPK signaling is directly caused by a CHI3L1-IL13RA2 co-binding, which leads to increased downstream MAPK and AKT signaling. This novel microenvironmental crosstalk highlights the crucial role of non-neoplastic cells in malignant brain tumors and opens up new perspectives for targeted therapies in glioblastoma.
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http://dx.doi.org/10.3390/cancers11101437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826948PMC
September 2019

DARK Classics in Chemical Neuroscience: Aminorex Analogues.

ACS Chem Neurosci 2018 10 5;9(10):2484-2502. Epub 2018 Oct 5.

Center for Physiology and Pharmacology, Institute of Pharmacology , Medical University of Vienna , Währingerstraße 13A , 1090 Vienna , Austria.

Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as "designer drugs" in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4'-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this Review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogues. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This Review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e., deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency, or the identity of the active ingredients remains obscure to NPS users.
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http://dx.doi.org/10.1021/acschemneuro.8b00415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711PMC
October 2018

The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters.

Neuropharmacology 2018 08 23;138:282-291. Epub 2018 Jun 23.

Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria; Center for Addiction Research and Science, Medical University Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria. Electronic address:

(±)-cis-4,4'-Dimethylaminorex (4,4'-DMAR) is a new psychoactive substance (NPS) that has been associated with 31 fatalities and other adverse events in Europe between June 2013 and February 2014. We used in vitro uptake inhibition and transporter release assays to determine the effects of 4,4'-DMAR on human high-affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). In addition, we assessed its binding affinities to monoamine receptors and transporters. Furthermore, we investigated the interaction of 4,4'-DMAR with the vesicular monoamine transporter 2 (VMAT2) in rat phaeochromocytoma (PC12) cells and synaptic vesicles prepared from human striatum. 4,4'-DMAR inhibited uptake mediated by human DAT, NET or SERT, respectively in the low micromolar range (IC values < 2 μM). Release assays identified 4,4'-DMAR as a substrate type releaser, capable of inducing transporter-mediated reverse transport via DAT, NET and SERT. Furthermore, 4,4'-DMAR inhibited both the rat and human isoforms of VMAT2 at a potency similar to 3,4-methylenedioxymethylamphetamine (MDMA). This study identified 4,4'-DMAR as a potent non-selective monoamine releasing agent. In contrast to the known effects of aminorex and 4-methylaminorex, 4,4'-DMAR exerts profound effects on human SERT. The latter finding is consistent with the idea that fatalities associated with its abuse may be linked to monoaminergic toxicity including serotonin syndrome. The activity at VMAT2 suggests that chronic abuse of 4,4'-DMAR may result in long-term neurotoxicity.
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http://dx.doi.org/10.1016/j.neuropharm.2018.06.018DOI Listing
August 2018

Improved Prosthetic Control Based on Myoelectric Pattern Recognition via Wavelet-Based De-Noising.

IEEE Trans Neural Syst Rehabil Eng 2018 02;26(2):506-514

Real-time inference of human motor volition has great potential for the intuitive control of robotic devices. Toward this end, myoelectric pattern recognition (MPR) has shown promise in the control of prosthetic limbs. Interfering noise and susceptibility to motion artifacts have hindered the use of MPR outside controlled environments, and thus represent an obstacle for clinical use. Advanced signal processing techniques have been previously proposed to improve the robustness of MPR systems. However, the investigation of such techniques have been limited to offline implementations with long time windows, which makes real-time use unattainable. In this work, we present a novel algorithm using discrete and stationary wavelet transforms for MPR that can be executed in real-time. Our wavelet-based de-noising algorithm outperformed conventional band-pass filtering (up to 100 Hz) and improved real-time MPR in the presence of motion artifacts, as measured by the motion test. Improved signal-to-noise ratio was found not to be crucial in offline MPR, as machine learning algorithms can integrate high but consistent noise as part of the signal. However, varying interference is expected to occur in real life where signal processing algorithms, as the one introduced in this paper, would potentially have a positive impact. Furthermore implementation of these algorithms in a prosthetic embedded system is required to validate their feasibility and usability during activities of the daily living.
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http://dx.doi.org/10.1109/TNSRE.2017.2771273DOI Listing
February 2018