A Novel Rat Infant Model of Medial Temporal Lobe Epilepsy Reveals New Insight into the Molecular Biology and Epileptogenesis in the Developing Brain.

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.p.) on days 9, 11, and 15 post partum (pp). The model had a survival rate of >80% and exhibited characteristic spontaneous recurrent electrographic seizures (SRES) in both the hippocampus and cortex that persisted into adulthood. Using implantable video-EEG radiotelemetry, we quantified a complex set of seizure parameters that demonstrated the induction of chronic electroencephalographic seizure activity in our InfRPil-mTLE model, which predominated during the dark cycle. We further analyzed selected candidate genes potentially relevant to epileptogenesis using a RT-qPCR approach. Several candidates, such as the low-voltage-activated Ca2+ channel Cav3.2 and the auxiliary subunits ß 1 and ß 2, which were previously reported to be upregulated in the hippocampus of the adult pilocarpine mTLE model, were found to be downregulated (together with Cav2.1, Cav2.3, M1, and M3) in the hippocampus and cortex of our InfRPil-mTLE model. From a translational point of view, our model could serve as a blueprint for childhood epileptic disorders and further contribute to antiepileptic drug research and development in the future.

Introduction of ICD-11 in Germany: Seizing opportunities together. / ICD-11 Einführung in Deutschland: Gemeinsam die Chance nutzen.

With the new ICD-11 developed by the WHO and translated into German for use in Germany by the Federal Institute for Drugs and Medical Devices, the German healthcare system is facing a change that is more than a simple change of a medical coding system. The ICD-11 modernises the coding system, for example, by including new, separate health conditions such as sleep-wake disorders and conditions related to sexual health, thus making the corresponding diseases more visible. The ICD-11 is more precise than the ICD-10: it allows cross-referencing between diagnoses, symptoms, functionality and locations and partially abandons the strict hierarchy of the ICD-10. In addition, a greater number of rare diseases are represented with their own specific code than was previously possible with ICD-10. Finally, the ICD-11 is also significantly more "modern" than the ICD-10 (which dates back to pre-digital times) in that it enables new, digitally-supported processes, such as keywords flexibility and sustainability when updating the system as well as actual coding at the point of care. The switch to ICD-11 can be a great opportunity for the German healthcare system that should not be missed. It will benefit health service research, which at best will be able to work with much more detailed and correct data sets. But medical care will also benefit because the ICD-11 reflects current medical knowledge. In addition, certain illnesses will be removed from the psychiatric category, meaning that those affected will no longer be stigmatised by their classification in the ICD. The improved coding of diagnoses will ultimately also support guideline-based treatments. However, the changeover is only the first step. The challenges - also for health service research - include in particular the latency of introduction and uniform use as well as the necessary change in coding habits. For ICD-11 to be a success in Germany, authorities, the medical profession, payers and patients must work together on strategies to ensure not only a rapid but also a comprehensive implementation that maximises the potential of ICD-11.

[Establishment of the new "Health Data Lab" to provide data for science]. / Aufbau des neuen "Forschungsdatenzentrums Gesundheit" zur Datenbereitstellung für die Wissenschaft.

The analysis of real-world data (RWD) has become increasingly important in health research in recent years. With the BfArM Health Data Lab (HDL), which is currently being set up, researchers will in future be able to gain access to routine data from the statutory health insurance of around 74 million people in Germany. Data from electronic patient records can also be made available for research prospectively. In doing so, the Health Data Lab guarantees the highest data protection and IT security standards. The digital application process, the provision of data in secure processing environments as well as the features supporting the analyses such as catalogues of coding systems, a point-and-click analysis tool and predefined standard analyses increase user-friendliness for researchers. The use of the extensive health data accessible at HDL will open a wide range of future possibilities for improving the health system and the quality of care. This article begins by highlighting the advantages of the HDL and outlining the opportunities that the RWD offers for research in healthcare and for the population. The structure and central aspects of the HDL are explained afterwards. An outlook on the opportunities of linking different data is given. What the application and data usage processes at the HDL will look like is illustrated using the example of fictitious possibilities for analysing long COVID based on the routine data available at the HDL in the future.

Cav3 T-Type Voltage-Gated Ca2+ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on Pharmacotherapy and Pharmacovigilance.

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 processes. In particular, HVA Cav2.3 R-type and LVA Cav3 T-type Ca2+ channels are expressed in the medial septum-diagonal band of Broca (MS-DBB), hippocampal interneurons, and pyramidal cells, and ablation of both channels was proven to severely modulate theta activity. Importantly, Cav3 Ca2+ channels contribute to rebound burst firing in septal interneurons. Consequently, functional impairment of T-type Ca2+ channels, e.g., in null mutant mouse models, caused tonic disinhibition of the septohippocampal pathway and subsequent enhancement of hippocampal theta activity. In addition, impairment of GABA A/B receptor transcription, trafficking, and membrane translocation was observed within the septohippocampal system. Given the recent findings that amyloid precursor protein (APP) forms complexes with GABA B receptors (GBRs), it is hypothesized that T-type Ca2+ current reduction, decrease in GABA receptors, and APP destabilization generate complex functional interdependence that can constitute a sophisticated proamyloidogenic environment, which could be of potential relevance in the etiopathogenesis of Alzheimer's disease (AD). The age-related downregulation of T-type Ca2+ channels in humans goes together with increased Aß levels that could further inhibit T-type channels and aggravate the proamyloidogenic environment. The mechanistic model presented here sheds new light on recent reports about the potential risks of T-type Ca2+ channel blockers (CCBs) in dementia, as observed upon antiepileptic drug application in the elderly.

Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives.

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 mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, ß-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

[Digitization of the healthcare system: the BfArM's contribution to the development of potential]. / Beitrag des BfArM zur Potenzialentfaltung der Digitalisierung im Gesundheitswesen ­ digital readiness@BfArM.

Digitalization is a clear megatrend of our time, also in the health sector, which is currently experiencing enormous acceleration due to the COVID-19 pandemic in addition to paving the way due to changes in the legal framework. Looking to the future, this trend will contribute to further digitalization and the merging of individual digital products, including medicinal products and medical devices, into a digital ecosystem. This will be supported by ever-shorter development cycles and technological progress. Digitization will not only strengthen patient sovereignty, but also enable more patient-centered medicine; artificial intelligence will improve and accelerate diagnoses and will contribute to a better understanding of disease patterns and underlying mechanisms or causes.In order to continue to enable innovations in the future, to focus on emerging trends, and, above all, to further improve patient safety, the BfArM is contributing in many places to transforming the opportunities associated with digitalization into possibilities - without losing sight of the risks. The following is an overview of how, for example, the expansion of the Research Data Center, activities addressing interoperability, research projects using artificial intelligence, (inter-)national cooperation, the utilization and inclusion of "Real World Data" in our benefit/risk assessments, and the evaluation of digital health and digital care applications among other activities of the BfArM contribute to "digital readiness" in Germany and Europe.

Functional implications of Cav 2.3 R-type voltage-gated calcium channels in the murine auditory system - novel vistas from brainstem-evoked response audiometry.

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, Cav 1.3 L-type VGCCs gathered most attention as their ablation causes congenital deafness. However, isolated patch-clamp investigation and localization studies repetitively suggested that Cav 2.3 R-type VGCCs are also expressed in the cochlea and further components of the ascending auditory tract, pointing to a potential functional role of Cav 2.3 in hearing physiology. Thus, we performed auditory profiling of Cav 2.3+/+ controls, heterozygous Cav 2.3+/- mice and Cav 2.3 null mutants (Cav 2.3-/- ) using brainstem-evoked response audiometry. Interestingly, click-evoked auditory brainstem responses (ABRs) revealed increased hearing thresholds in Cav 2.3+/- mice from both genders, whereas no alterations were observed in Cav 2.3-/- mice. Similar observations were made for tone burst-related ABRs in both genders. However, Cav 2.3 ablation seemed to prevent mutant mice from total hearing loss particularly in the higher frequency range (36-42 kHz). Amplitude growth function analysis revealed, i.a., significant reduction in ABR wave WI and WIII amplitude in mutant animals. In addition, alterations in WI -WIV interwave interval were observed in female Cav 2.3+/- mice whereas absolute latencies remained unchanged. In summary, our results demonstrate that Cav 2.3 VGCCs are mandatory for physiological auditory information processing in the ascending auditory tract.

Master protocols in clinical trials: a universal Swiss Army knife?

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 development and to reduce futility, their use poses challenges to ethics committees, patients, study investigators, and competent authorities during the review and authorisation process of a clinical trial application. In this Personal View, we review the experiences of clinical trial applications from two European medical regulators-the Danish Medicines Agency and the German Federal Institute for Drugs and Medical Devices. We view master protocols as a good opportunity to identify new treatment options more quickly, particularly for patients with cancer. However, the complexity of trial documentation, the amount of information resulting from sub-trials, and the volume of changes and amendments made to clinical trial applications can cause issues during trial supervision, and during the analysis and review of a corresponding application for marketing authorisation. We draw attention to the potential issues arising from these trial concepts and propose possible solutions to avoid problems during clinical trial authorisation and trial conduct.

[Cannabis for medical purposes : Impact of the law of 6 March 2017 on physicians]. / Cannabis als Medizin : Auswirkungen des Gesetzes vom 6. März 2017 auf die Ärzteschaft.

The law on the amendment of the narcotics law and other regulations, which was accepted by consensus by the German Parliament, significantly expanded the options for the use of cannabis-based medicinal products. In individual cases, already approved cannabis-based medicinal products can also be prescribed outside the approved indication at the expense of the statutory health insurance funds (GKV). The cost of treatment with cannabis flowers and extracts as well as dronabinol, which are not approved under the drug law, will also be covered by the GKV upon application. Physicians must advise their patients on the options of treatment with cannabis-based medicinal products and support them in applying for reimbursement. The prescription of unauthorized medical cannabis products poses particular challenges, as there is no summary of product characteristics that is mandatory for authorized finished products. In addition, physicians are obliged to participate in an accompanying survey. To this end, they must send data to the Federal Institute for Drugs and Medical Devices providing information about treatment with cannabis-based medicinal products. When prescribing medical cannabis products as defined in the Act of 6 March 2017 amending the law on narcotic drugs and other regulations, physicians assume a special responsibility that goes far beyond the responsibility for the use of authorized finished medicinal products.

Precision pharmacology for Alzheimer's disease.

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 and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective disease-modifying pathway-based targeted therapies. PP is based on an exploratory and integrative strategy to complex diseases such as brain proteinopathies including AD, aimed at identifying simultaneous aberrant molecular pathways and predicting their temporal impact on the systems levels. The depiction of pathway-based molecular signatures of complex diseases contributes to the accurate and mechanistic stratification of distinct subcohorts of individuals at the earliest compensatory stage when treatment intervention may reverse, stop, or delay the disease. In addition, individualized drug selection may optimize treatment safety by decreasing risk and amplitude of side effects and adverse reactions. From a methodological point of view, comprehensive "omics"-based biomarkers will guide the exploration of spatio-temporal systems-wide morpho-functional shifts along the continuum of AD pathophysiology, from adaptation to irreversible failure. The Alzheimer Precision Medicine Initiative (APMI) and the APMI cohort program (APMI-CP) have commenced to facilitate a paradigm shift towards effective drug discovery and development in AD.