Publications by authors named "Klitgaard H"
Article Synopsis
- * Current treatments mainly provide symptom relief, and effective therapies to modify the disease and protect neurons are limited.
- * The nuclear factor-erythroid 2-related factor 2 (NRF2) plays a key role in defending cells from damage, making it a promising target for new treatments aimed at addressing neurodegeneration's root causes.
Objectives: This review aims to analyse the published data on preclinical and human experimental and clinical adenosine modulation for pain management. We summarise the translatability of the adenosine pathway for further drug development and aim to reveal subgroups of pain patients that could benefit from targeting the pathway.
Content: Chronic pain patients suffer from inadequate treatment options and drug development is generally impaired by the low translatability of preclinical pain models.
Article Synopsis
- Drug discovery for epilepsy started with potassium bromide in 1857 and evolved through phenotypic screening tests, but current antiseizure medications still struggle with drug resistance and lack disease-modifying treatments.
- RNA-based drugs have emerged as a promising new approach to address these issues, targeting both noncoding RNAs and messenger RNAs to potentially modify diseases and overcome drug resistance.
- The paper discusses various therapeutic strategies using RNA therapeutics for different types of epilepsy, including sporadic cases, drug-resistant forms, and childhood monogenic epilepsies.
Background: Antiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer C-UCB-J.
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- * The text highlights strategies for delivering these RNA-based drugs to the central nervous system (CNS) and discusses recent clinical advancements specifically for neurological and neuromuscular disorders.
- * Key abbreviations related to the topic include ALS for Amyotrophic Lateral Sclerosis, AD for Alzheimer's Disease, and CNS for Central Nervous System, indicating the range of conditions addressed by these innovative therapies.
Purpose: To understand the currently available post-marketing real-world evidence of the incidences of and discontinuations due to the BAEs of irritability, anger, and aggression in people with epilepsy (PWE) treated with the anti-seizure medications (ASMs) brivaracetam (BRV), levetiracetam (LEV), perampanel (PER), and topiramate (TPM), as well as behavioral adverse events (BAEs) in PWE switching from LEV to BRV.
Methods: A systematic review of published literature using the Cochrane Library, PubMed/MEDLINE, and Embase was performed to identify retrospective and prospective observational studies reporting the incidence of irritability, anger, or aggression with BRV, LEV, PER, or TPM in PWE. The incidences of these BAEs and the rates of discontinuation due to each were categorized by ASM, and where possible, weighted means were calculated but not statistically assessed.
Purpose Of Review: Individuals with metabolically unhealthy normal weight (MUNW) have an adverse cardiometabolic risk factor profile in the absence of excess body weight, and increased risk for diabetes and heart disease. We critically review some physiological traits and lifestyle characteristics of the MUNW phenotype.
Recent Findings: The prevalence of MUNW varies considerably around the world and among ethnicities, partly because of different definitions; on average, this phenotype affects about ~ 30% of normal weight persons globally.
Article Synopsis
- * There are existing medications that show promise in preventing or modifying post-injury epilepsy, with some having favorable side effect profiles, including atorvastatin and certain antiseizure medications like levetiracetam and topiramate.
- * The challenge in developing preventive treatments lies in the variability of preclinical studies in terms of injury types, dosing, and evaluation methods, making it hard to determine the most effective drugs for clinical trials.
Article Synopsis
- Padsevonil is a novel antiepileptic drug that works by binding to synaptic vesicle protein 2 (SV2) and GABA receptors, influencing both pre- and postsynaptic activities to control seizures.
- In various seizure models, padsevonil showed strong protective effects against seizures, especially in acute and chronic epilepsy models, while outperforming other antiepileptic drugs in certain tests.
- Unlike diazepam, padsevonil did not lead to tolerance in its antiseizure effects, suggesting a potentially promising choice for epilepsy treatment with a favorable efficacy and tolerability profile.
Objective: Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer C-UCB-J (EP0074; NCT02602860).
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- - Acquired epilepsies usually result from acute brain injuries like trauma, strokes, or infections, with current treatments effective in only 60-70% of cases, which still focus on symptoms rather than prevention.
- - Recent research is looking into key causes of epilepsy, such as inflammation, neuron loss, and circuit changes, to find potential targets for new treatments and understand similarities between human and animal models of epilepsy.
- - Common risk factors for developing epilepsy after brain injuries include severe injuries, bleeding, and early seizures, with noticeable brain changes like microglial activation and neuron loss appearing in many cases.
Brivaracetam (BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A (SV2A), recently approved as adjunctive treatment for drug-refractory partial-onset seizures in adults. BRV binds SV2A with higher affinity than levetiracetam (LEV), and was shown to have a differential interaction with SV2A. Because LEV was reported to interact with multiple excitatory and inhibitory ligand-gated ion channels and that may impact its pharmacological profile, we were interested in determining whether BRV directly modulates inhibitory and excitatory ionotropic receptors in central neurons.
View Article and Find Full Text PDFObjective: To evaluate acute and long-term effects of intravenous brivaracetam (BRV) and BRV + diazepam (DZP) combination treatment in a rat model of self-sustaining status epilepticus (SSSE).
Methods: Rats were treated with BRV (10 mg/kg) 10 min after initiation of perforant path stimulation (PPS) as early treatment; or BRV (10-300 mg/kg), DZP (1 mg/kg), or BRV (0.3-10 mg/kg) + DZP (1 mg/kg) 10 min after the end of PPS (established SSSE).
The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models.
View Article and Find Full Text PDFDespite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures.
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- The study aimed to evaluate how quickly the antiepileptic drug brivaracetam (BRV) penetrates the brain compared to levetiracetam (LEV), focusing on factors like brain entry rate and onset of action.
- Various methods, including permeation studies in cells, animal dosing, and imaging techniques, were used to measure and compare the distribution and effects of BRV and LEV.
- Results showed that BRV entered the brain significantly faster than LEV and had a quicker effect on seizures, suggesting BRV could be more effective in treating acute seizures due to its rapid brain penetration.
Article Synopsis
- - Contemporary epilepsy research aims to find therapies that can stop recurrent seizures, particularly in patients with conditions like brain injuries or genetic predispositions.
- - The review discusses various therapies being studied, including marketed antiseizure drugs and those targeting immune responses, oxidative stress, and specific cellular pathways, all with potential antiepileptogenic effects that extend beyond treatment.
- - While clinical trials have yet to show disease-modifying effects of current antiseizure drugs, promising results from animal studies and new strategies targeting specific signaling pathways offer hope for developing short-term treatments that could prevent spontaneous seizures.
Article Synopsis
- * Recent advancements in understanding epilepsy's mechanisms and drug resistance have opened doors for developing better treatments.
- * Future drug development might benefit from collaboration between academia and industry, focusing on targeted approaches and innovative trial designs.
There is a pressing need to address the current major gaps in epilepsy treatment, in particular drug-resistant epilepsy, antiepileptogenic therapies, and comorbidities. A major concern in the development of new therapies is that current preclinical testing is not sufficiently predictive for clinical efficacy. Methodologic limitations of current preclinical paradigms may partly account for this discrepancy.
View Article and Find Full Text PDFSeveral preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic.
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- A working group composed of clinicians and researchers was set up to tackle issues in epilepsy treatment and explore new therapeutic approaches.
- They identified the necessity for improved animal models that better reflect human conditions for testing antiseizure drugs (ASDs), and recognized significant gaps in treatment for specific seizure types, like tonic-atonic and myoclonic seizures.
- The group pointed out the potential for developing new therapies, especially for both common and rare epilepsy syndromes, and emphasized that incorporating biomarkers could enhance the effectiveness of clinical trials for disease-modifying treatments.
Aims: Synaptic vesicle proteins 2 (SV2) are neuronal vesicles membrane glycoproteins that appear as important targets in the treatment of partial and generalized epilepsies. Therefore, we analysed the expression of SV2 isoforms in the hippocampus of patients with temporal lobe epilepsy (TLE).
Methods: SV2A, SV2B and SV2C immunostaining and QuantiGene branched DNA assay were performed on biopsies from 31 consecutive TLE patients with mesial temporal sclerosis (MTS) and compared with 10 autopsy controls.
Epilepsy therapy: anticonvulsants, lessons learned and unmet medical needs. Interview by Rona Williamson.
Expert Rev Neurother
January 2013
Article Synopsis
- * He has published over 80 peer-reviewed papers and holds memberships in key epilepsy organizations, including the US National Institute of Health's epilepsy advisory committee, reflecting his significant contributions to the field.
- * Klitgaard has worked in antiepileptic drug discovery for over 20 years, with experience at Novo Nordisk A/S and UCB Pharma, and is actively involved in developing new clinical and preclinical AED candidates.
Article Synopsis
- New antiepileptic drugs (AEDs) introduced in the last two decades have improved treatment options and reduced risks but still don't effectively address drug-refractory epilepsy or offer a cure.
- There is a need for new preclinical screening strategies to discover AEDs that target the challenges in managing drug-refractory epilepsy, using insights from genetics and other related fields.
- Implementing integrated strategies for trial design and identifying relevant biomarkers can enhance the drug development process and improve the chances of clinical efficacy.