Karl Broich

Bundesinstitut für Arzneimittel und Medizinprodukte

Although several adult rat models of medial temporal lobe epilepsy (mTLE) have been described in detail, our knowledge of mTLE epileptogenesis in infant rats is limited. Here, we present a novel infant rat model of mTLE (InfRPil-mTLE) based on a repetitive, triphasic injection regimen consisting of low-dose pilocarpine administrations (180 mg/kg. i...

Objectives The G72 mouse model of schizophrenia represents a well-known model that was generated to meet the main translational criteria of isomorphism, homology and predictability of schizophrenia to a maximum extent. In order to get a more detailed view of the complex etiopathogenesis of schizophrenia, whole genome transcriptome studies turn out...

A variety of Alzheimer’s disease (AD) mouse models has been established and characterized within the last decades. To get an integrative view of the sophisticated etiopathogenesis of AD, whole genome transcriptome studies turned out to be indispensable. Here we carried out microarray data collection based on RNA extracted from the retrosplenial cor...

Die Analyse von Real-world-Daten (RWD) hat in der Gesundheitsforschung der vergangenen Jahre eine immer größere Bedeutung gewonnen. Mit dem im Aufbau befindlichen Forschungsdatenzentrum Gesundheit („FDZ Gesundheit“) werden Forschende künftig Zugang zu Routinedaten der gesetzlichen Krankenversicherungen von rund 74 Mio. Menschen in Deutschland erhal...

A variety of Alzheimer disease (AD) mouse models has been established and characterized within the last decades. These models are generated to meet the principal criteria of AD isomorphism, homology and predictability to a maximum extent. To get an integrative view of the sophisticated etiopathogenesis of AD, whole genome transcriptome data analysi...

Zusammenfassung Hintergrund Real-world-Daten (RWD) und die aus ihnen durch statistisch-epidemiologische Analysen abgeleitete Real-world-Evidenz (RWE) spielen eine vielversprechende und zunehmend relevante Rolle bei regulatorischen Entscheidungsfindungen entlang des Produktlebenszyklus von Arzneimitteln. Ziel der Arbeit Es wird ein Überblick über...

Voltage-gated Ca2+ channels (VGCCs) were reported to play a crucial role in neurotransmitter release, dendritic resonance phenomena and integration, and the regulation of gene expression. In the septohippocampal system, high- and low-voltage-activated (HVA, LVA) Ca2+ channels were shown to be involved in theta genesis, learning, and memory processe...

In den folgenden Abschnitten dieses Kapitels werden wir uns damit befassen, was ein Arzneimittel ist, wie es zur Marktzulassung kommt und auf welchen Wegen ein Arzneimittel heutzutage zum Patienten gelangt. Der Schwerpunkt dieses Kapitels wird hierbei auf der Erläuterung eines wichtigen Ziels der Gesundheitspolitik liegen – „den Bürgern müssen im B...

Zusammenfassung Die Digitalisierung stellt auch im Gesundheitsbereich einen eindeutigen Megatrend dar, der neben der Wegbereitung durch geänderte rechtliche Rahmenbedingungen auch durch die Coronapandemie eine enorme Beschleunigung erfahren hat. Mit Blick in die Zukunft wird dieser Trend durch immer kürzere Entwicklungszyklen und technologischen Fo...

High voltage-activated Cav2.3 R-type Ca²⁺ channels and low voltage-activated Cav3.2 T-type Ca²⁺ channels were reported to be involved in numerous physiological and pathophysiological processes. Many of these findings are based on studies in Cav2.3 and Cav3.2 deficient mice. Recently, it has been proposed that inbreeding of Cav2.3 and Cav3.2 deficie...

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of...

Background: N-nitrosodimethylamine (NDMA) has been classified as a probable human carcinogen and has been found as a contaminant in valsartan, an antihypertensive drug. Potential carcinogenic effects from the consumption of NDMA-contaminated valsartan have not been analyzed to date in large-scale cohort studies. We therefore carried out the study...

This article provides raw relative electroencephalographic (EEG) power, temperature and activity data from controls and Cav3.2 deficient mice. Radiotransmitter implantation was carried out in male experimental mice under ketamine/xylazine narcosis. Following a recovery period, radiotelemetric EEG recordings from the hippocampal CA1 region were obta...

T-type Ca ²⁺ channels are assumed to contribute to hippocampal theta oscillations. We used implantable video-EEG radiotelemetry and qPCR to unravel the role of Ca v 3.2 Ca ²⁺ channels in hippocampal theta genesis. Frequency analysis of spontaneous long-term recordings in controls and Ca v 3.2 −/− mice revealed robust increase in relative power in t...

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mai...

Neuroinflammation, a key early pathomechanistic alteration of Alzheimer's disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a l...

β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer's disease (AD). A robust body of evidence demonstrates an associ...

Die zum 1. Januar 2011 in Kraft getretene Frühe Nutzenbewertung neu zugelassener Arzneimittel mit innovativen Wirkstoffen und neuen Anwendungsgebieten stellt alle Beteiligten auch heute noch vor Herausforderungen. Der Beitrag betrachtet neben Definitionen, regulatorischen Anforderungen an Zulassung und Frühe Nutzenbewertung auch das Zusammenspiel z...

Once first Alzheimer's disease (AD) disease-modifying therapies will become available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers needs to be advanced. Besides establ...

Objectives Voltage-gated Ca²⁺ channels (VGCCs) are of central relevance in regulating Ca²⁺ influx into living cells. The low-voltage activated (LVA) Cav3 T-type Ca²⁺ channels are widely distributed throughout the brain including the peripheral auditory system and ascending auditory tract. Their exact role in auditory information processing is still...

Voltage‐gated Ca2+ channels (VGCCs) are considered to play a key role in auditory perception and information processing within the murine inner ear and brainstem. In the past, Cav1.3 L‐type VGCCs gathered most attention as their ablation causes congenital deafness. However, isolated patch‐clamp investigation and localisation studies repetitively su...

Introduction: Successful development of effective β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudi...

Background In Germany, physicians who prescribe cannabis-based medicines at the expense of the statutory health insurance are obliged to take part in an accompanying survey. Pain was the most commonly reported diagnosis, making an interim evaluation for the indication of pain feasible. Methods Patient-related data was transmitted to the German Fed...

Mit dem vom Bundestag einstimmig beschlossenen Gesetz zur Änderung betäubungsmittelrechtlicher und anderer Vorschriften wurden die Möglichkeiten zur Verwendung von Cannabisarzneimitteln deutlich erweitert. Bereits zugelassene Cannabisarzneimittel können im Einzelfall auch außerhalb der zugelassenen Indikation zulasten der gesetzlichen Krankenkassen...

Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomar...

Master protocols combine several sub-trials, each with their own research objectives, which is usually presented as one single clinical trial application. Master protocols have become increasingly popular in oncology and haematology, as either basket, umbrella, or platform trials. Although master protocols are intended to accelerate drug developmen...

Introduction: Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. / Methods: We investigated whether plasma concentrations of the Aβ1–40/Aβ1–42 ratio, assessed using t...

Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state function...

Introduction: Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the Aβ1-40/Aβ1-42 ratio, assessed using...

Voltage-gated Ca ²⁺ channels (VGCCs) play key roles in auditory perception and information processing within the inner ear and brainstem. Pharmacological inhibition of low voltage-activated (LVA) T-type Ca ²⁺ channels is related to both age- and noise induced hearing loss in experimental animals and may represent a promising approach to the treatme...

This paper presents the importance of using appropriate methods to select samples and of testing hypotheses with suitable statistical methods. It explains special evaluation procedures, including the observed case analysis and last observation carried forward analysis, and describes the value of various meta-analytical approaches. The paper ends by...

This data article provides raw auditory evoked brainstem responses (ABRs) from controls and Cav2.3 transgenics, i.e. heterozygous Cav2.3+/- and Cav2.3-/- null mutants. Gender specific ABR recordings were performed in age-matched animals under ketamine/xylazine narcosis. Data presented here include ABRs upon both click and tone burst presentation in...

The paper presents the range of methodological options for clinical treatment research on psychopharmaceuticals. The prospective, randomised, double-blind, placebo-controlled trial, performed as a parallel group comparison, is thereby considered to be the most informative method overall. All other methods have various disadvantages. Key words: Psyc...

Judicious use of Real World Data (RWD) is expected to make all steps in the development and utilisation of pharmaceuticals more effective and efficient, including research and development, regulatory decision making, health technology assessment, pricing and reimbursement decisions and treatment. A ‘learning healthcare system’ based on electronic h...

Background: There is evidence that uric acid may have antioxidant and neuroprotective effects and might therefore alter the risk for neurodegenerative diseases such as dementia. So far, the relation between serum uric acid (SUA) levels or hyperuricemia and dementia remains elusive. Most studies focused on the disease or SUA levels. Effects of anti...

Antiepileptic drugs can effect cognition by suppressing neuronal excitability and increasing inhibitory neurotransmission. Previous studies report acute cognitive adverse effects (CAE) of some but not all AEDs. The association of AED use and risk of dementia has rarely been investigated. To our knowledge there is only one study so far that analyzes...

en This letter comments on the letters by Rani A. Sarkis et al and Christoph Helmstaedter et al.

In an ongoing project supported by the Federal Ministry of Health (BMG) off-label use of pharmaceuticals with high prescription rates is investigated in a database comprising all citizens covered by public sick funds, i. e. some 89 % of the German population. The focus is on prevalences and indications as well as on the identification of off-label...

Introduction Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers. Methods Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2-deoxy-2-[fluorine-18]fluoro-D-glu...

Introduction: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and h...

Erratum zu: Bundesgesundheitsblatt 2018 10.1007/s00103-018-2732-0 Wir möchten Sie darauf hinweisen, dass in der Originalpublikation des Artikels der englische Artikeltitel leider aufgrund eines Fehlers im Produktionsprozess nicht korrekt dargestellt wurde. Richtig lautet er: Antibiotic …

In einem vom Bundesministerium für Gesundheit geförderten Projekt wird der Off-Label-Use häufig verordneter Arzneimittel in einer Vollerfassung der Abrechnungsdaten der gesetzlichen Krankenversicherung (Daten nach §§303aff. SGB V) untersucht, um einerseits Erkenntnisse über seine Häufigkeit und Art zu gewinnen und andererseits Ansätze für gezielte...

Objectives To evaluate the association between regular antiepileptic drug (AED) use and incident dementia. Design Case‐control analysis. Setting Finnish public health register and German health insurance data. Participants Individuals with dementia of any type (German data, N=20,325) and Alzheimer's disease (AD; Finnish data, N=70,718) were matc...

The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation...

Im vorliegenden Auszug der Übersicht werden die verschiedenen Untergruppen der hochspannungsaktivierten L- und Non-L-Typ sowie der niederspannungsaktivierten T-Typ Ca2+-Kanäle vorgestellt und für alle bekannten zehn Cav-α1-Untereinheiten die pharmakologischen Merkmale herausgearbeitet. Auch die akzessorischen Untereinheiten finden hierbei Berücksic...

Calcium ions play an essential role in the structural and functional integrity of cells. Multiple ion channels and transporters have been developed during evolution and exhibit complex temporal and spatial regulation of calcium influx and efflux into and out of living cells. Processes like excitation-secretion coupling, excitationcontraction coupli...

In an ongoing project supported by the Federal Ministry of Health (BMG) off-label-use of pharmaceuticals with high prescription rates is investigated in a database comprising all citizens covered by public sick funds. The focus is on prevalences and indications as well as on the identification of off-label use specifically addressing rare diseases...

In an ongoing project supported by the Federal Ministry of Health (BMG) off-label-use of pharmaceuticals with high prescription rates is investigated in a database comprising all citizens covered by public sick funds, i. e. almost 90% of the German population, with a focus on prevalences and indications as well as on the identification of off-label...

In an ongoing project supported by the Federal Ministry of Health (BMG) off-label-use of phar-maceuticals with high prescription rates is investigated in a database comprising all citizens covered by public sick funds, i. e. almost 90% of the German population. The focus is on prevalences and indications as well as on the identification of off-labe...

Pharmacological neuroenhancement and mood enhancement are gaining tremendous importance in society. The main motivation for neuroenhancement and mood enhancement is the anticipated increase in attention and vigilance, better performance in learning and memory and mood stability to meet the complex demands of an exacerbating meritocracy. Most users...

Theta activity is generated in the septohippocampal system and can be recorded using deep intrahippocampal electrodes and implantable electroencephalography (EEG) radiotelemetry or tether system approaches. Pharmacologically, hippocampal theta is heterogeneous (see dualistic theory) and can be differentiated into type I and type II theta. These ind...

Voltage-gated Ca²⁺ channels are of central relevance in mediating numerous intracellular and transcellular processes including excitation-contraction coupling, excitation secretion-coupling, hormone and neurotransmitter release and gene expression. The Cav2.3 R-type Ca²⁺ channel is a high-voltage activated channel which plays a crucial role in neur...

After intense scientific exploration and more than a decade of failed trials, Alzheimer’s disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shi...

Alzheimer’s disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study, an APPswePS1dE9 AD mouse model has been analyzed for motor cortex theta, beta and gamma frequency alterations using computerized 3D stereotaxic electrode positioning and implantable video-EEG radiotelemetry to perform long-t...

FFT based EEG analysis. Representative 10 sec EEG segments are displayed FFT based up to 70 Hz. Representative amplitude spectra [V] are displayed for male APPswePS1dE9 and control mice at the age of 14 wks for the dark cycle for both the active and inactive state. (PDF)

Relative cortical power of different EEG frequency bands during the dark cycle. Relative power values for both males and females are displayed using GraphPad Prism. Recordings which exhibited EMG artefacts (due to motor activity) or electrical artefacts and did not meet strict EEG quality criteria were not incorporated in the analysis (see Material...

Relative cortical power of different EEG frequency bands during the light cycle. Relative power values for both males and females are displayed using GraphPad Prism. Animals which exhibited EMG artefacts (due to motor activity) or electrical artefacts and did not meet strict EEG quality criteria were not incorporated in the analysis (see Materials...

Arzneimittel für Kinder und Jugendliche werden in Deutschland und Europa erst seit rund einem Jahrzehnt systematisch so erforscht, wie dies bei Erwachsenen schon seit Jahrzehnten erfolgt. Auch heute werden noch viele Arzneimittel bei Kindern ohne systematische pädiatrische Studien – zum Beispiel zur Dosierung oder zu Darreichungsformen – angewendet...

Atopic conditions (atopic dermatitis, rhinitis and asthma) belong to the most common non communicable diseases and are driven by chronic inflammatory reactions. They have a strong impact on the quality of life and represent a substantial and growing socio-economic burden. Interestingly, there is an increasing interest in the development of new ther...

Background Researchers have gained substantial insight into mechanisms of synaptic transmission, hyperexcitability, excitotoxicity and neurodegeneration within the last decades. Voltage-gated Ca²⁺ channels are of central relevance in these processes. In particular, they are key elements in the etiopathogenesis of numerous seizure types and epilepsi...

Abstract: The new European regulation for in vitro diagnostics (IVD) divides the certification of IVD including companion diagnostics (CDx) by notified bodies (NB) from the market authorization of medicines. With the new regulation, CDx will require conformity assessment which is expected to include clinical evidence by NB. This is a significant ch...

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medi...

Objective To evaluate the association between BDZR prescription and incident any dementia in a large German claims data set.

Background: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or...

Background: Although there is still no cure for multiple sclerosis (MS), the introduction of several innovative drugs with modes of action different from that of the existing drug arsenal and the progress in monitoring disease progression by imaging and using biomarkers are currently causing a knowledge surge. This provides opportunities for impro...

Implantable EEG radiotelemetry is of central relevance in the neurological characterization of transgenic mouse models of neuropsychiatric and neurodegenerative diseases as well as epilepsies. This powerful technique does not only provide valuable insights into the underlying pathophysiological mechanisms, i.e., the etiopathogenesis of CNS related...

Regulation may contribute to high drug costs, but there are several ways in which regulators at the European Medicines Agency believe they can contribute to keeping drug spending sustainable, beginning with approving genetics and biosimilars more rapidly.