Cannabidiol: pharmacology and therapeutic targets

Psychopharmacology, Journal Year: 2020, Volume and Issue: 238(1), P. 9 - 28

Published: Nov. 21, 2020

Language: Английский

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Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

CNS Drugs, Journal Year: 2022, Volume and Issue: 36(10), P. 1079 - 1111

Published: Oct. 1, 2022

The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood significant neurodevelopmental comorbidities. latter include intellectual disability, delay, behavioural problems including attention-deficit hyperactivity disorder autism spectrum disorder, psychiatric anxiety depression, speech impairment sleep problems. Classical examples Dravet syndrome, Lennox–Gastaut syndrome tuberous sclerosis complex. mainstay treatment is multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated psychobehavioural adverse events, effects (negative or positive) on cognition sleep. We have performed targeted literature review commonly used to discuss latest evidence their behaviour, mood, cognition, sedation valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) everolimus. Bromide, felbamate other sodium channel are discussed briefly. Overall, current suggest that LEV, PER lesser extent BRV events aggressiveness irritability; TPM ZNS language cognitive dulling/memory Patients history comorbidities may more at risk developing events. Topiramate negative some aspects cognition; CBD, FFA, LTG positive effects, while remaining do not appear detrimental effect. All certain extent, which pronounced during uptitration. Cannabidiol, pregabalin improvements sleep, insomnia, VPA, TPM, LCM effects. There was variability for each ASM: many first-generation second-generation ASMs, there scant documented evidence; extensive use suggests favourable tolerability safety (e.g. VPA); third-generation tend most robust over several years (TPM, PER, ZNS, BRV), still being generated newer such as CBD FFA. Finally, we how variety factors affect behaviour untangling associations between underlying those challenging. In particular, enormous heterogeneity cognitive, impairments complex change naturally time; lack standardised instruments evaluating these outcomes encephalopathies, reliance subjective evaluations proxy (caregivers); regimes involving well drugs.

Language: Английский

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The Role of Glutamate Receptors in Epilepsy

Biomedicines, Journal Year: 2023, Volume and Issue: 11(3), P. 783 - 783

Published: March 4, 2023

Glutamate is an essential excitatory neurotransmitter in the central nervous system, playing indispensable role neuronal development and memory formation. The dysregulation of glutamate receptors glutamatergic system involved numerous neurological psychiatric disorders, especially epilepsy. There are two main classes receptor, namely ionotropic metabotropic (mGluRs) receptors. former stimulate fast neurotransmission, N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate; while latter G-protein-coupled that mediate activity via intracellular messenger systems. Glutamate, receptors, regulation astrocytes significantly pathogenesis acute seizure chronic Some receptor antagonists have been shown to be effective for treatment epilepsy, research clinical trials ongoing.

Language: Английский

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A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication

CNS Drugs, Journal Year: 2022, Volume and Issue: 36(3), P. 217 - 237

Published: Feb. 14, 2022

Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures cognitive dysfunction. The treatment challenging, not least because the are highly drug resistant, requiring multiple anti-seizure medications (ASMs), while some ASMs can exacerbate seizures. Initial treatments include broad-spectrum valproate (VPA), clobazam (CLB) in regions; however, they generally insufficient to control With this mind, three adjunct have been approved specifically for of patients with syndrome: stiripentol (STP) 2007 European Union 2018 USA, cannabidiol (CBD) 2018/2019 (in combination CLB Union) fenfluramine (FFA) 2020. These "add-on" therapies (mostly VPA/CLB) used as escalation therapies, choice dependent on availability different countries, patient characteristics caregiver preferences. Topiramate also frequently used, evidence efficacy syndrome, there anecdotal bromide, which Germany Japan. growing landscape be practical challenges clinicians, particularly issues associated polypharmacy. This guide provides an overview these main including their indications/contraindications, mechanism action, efficacy, safety tolerability profile, dosage requirements, laboratory clinical parameters evaluated. Standard blood counts, liver function tests, serum concentrations ASMs, monitoring growth children, well weight loss acceleration behavioural problems. Regular cardiac important FFA it has previously cases valve disease when adults at high doses (up 120 mg/day) phentermine therapy obesity. Importantly, no signs heart documented date low encephalopathies. In addition, potential drug–drug interactions consequences key consideration everyday practice. Interactions that potentially require adjustments alleviate adverse events following: STP + resulting increased plasma its active metabolite norclobazam may increase somnolence, interaction VPA gastrointestinal events. Cannabidiol bi-directional producing 7-OH-CBD somnolence sedation. CBD elevations transaminases taking concomitant VPA. between requires dose reduction FFA. Furthermore, administration topiramate and/or hyperammonaemia. Finally, we briefly describe other current trials.

Language: Английский

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The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

Antioxidants, Journal Year: 2022, Volume and Issue: 11(1), P. 157 - 157

Published: Jan. 14, 2022

One of the most important characteristics brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities oxygen, generating significant amounts reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders nervous system, where pathological processes such aberrant protein oxidation can ultimately lead cellular dysfunction death. Epilepsy, characterized by long-term predisposition epileptic seizures, one common neurological OS. Evidence shows that increased neuronal excitability-the hallmark epilepsy-is accompanied neuroinflammation an excessive production ROS; together, these factors likely key features seizure initiation propagation. This review discusses role OS in epilepsy, connection impact on synaptic function. Considering pharmacological treatment options for epilepsy limited heterogeneity disorders, we also introduce latest advances anti-epileptic drugs (AEDs) how they interact We conclude intertwined numerous physiological molecular mechanisms although causal relationship yet be established.

Language: Английский

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Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity

Neuron, Journal Year: 2023, Volume and Issue: 111(8), P. 1282 - 1300.e8

Published: Feb. 13, 2023

Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms pediatric epilepsies, but the mechanism(s) anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking pro-excitatory actions an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), G-protein-coupled receptor GPR55. However, impact LPI-GPR55 signaling inhibitory synapses and epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability evoked synaptic strength WT mice, while attenuating postsynaptic by decreasing GABAARγ2 gephyrin puncta. effects were eliminated pre-treatment absent after GPR55 deletion. Acute pentylenetrazole-induced elevated levels, chronic lithium-pilocarpine-induced potentiated LPI's effects. propose exerts potential dampening hyperexcitability.

Language: Английский

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Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(1), P. 71 - 71

Published: Jan. 10, 2024

Epilepsy represents a condition in which abnormal neuronal discharges or the hyperexcitability of neurons occur with synchronicity, presenting significant public health challenge. Prognostic factors, such as etiology, electroencephalogram (EEG) abnormalities, type and number seizures before treatment, well initial unsatisfactory effects medications, are important considerations. Although there several third-generation antiepileptic drugs currently available, their multiple side can negatively affect patient quality life. The inheritance etiology epilepsy complex, involving underlying genetic epigenetic mechanisms. Different neurotransmitters play crucial roles maintaining normal physiology different neurons. Dysregulations neurotransmission, due to transmitter levels changes receptors, result seizures. In this review, we address played by various receptors pathophysiology epilepsy. Furthermore, extensively explore neurological mechanisms involved development progression epilepsy, along its risk factors. highlight new therapeutic targets, pharmacological non-pharmacological strategies employed treatment epileptic syndromes, including drug interventions clinical trials related

Language: Английский

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Cannabidiol in the Treatment of Epilepsy

Clinical Drug Investigation, Journal Year: 2021, Volume and Issue: 41(3), P. 211 - 220

Published: Feb. 9, 2021

Anecdotal reports addressing the successful seizure treatment of severe epilepsies with cannabidiol (CBD) have increased both public interest and academic research. Placebo-controlled, randomized, controlled trials proved efficacy pharmaceutical-grade CBD in epilepsy treatment, thus leading to approval by US Food Drug Administration European Medicines Agency for seizures Dravet syndrome Lennox–Gastaut as well tuberous complex only. However, market is confusing because an array products different origins, purity, concentration available. Additionally, results from pivotal studies plant-derived, cannot simply be transferred other types or any origin. Because high demands expectations that patients their caregivers regarding CBD, information outlining proven facts potential risks essential. The aim this article thoroughly review available research data practical recommendations provide treating physician necessary counseling epilepsy.

Language: Английский

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Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies

CNS Drugs, Journal Year: 2021, Volume and Issue: 35(1), P. 61 - 83

Published: Jan. 1, 2021

Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses heterogenous group of aetiologies, with no single genetic cause. It characterised by multiple seizure types, abnormal EEG generalised slow spike wave discharges cognitive impairment, associated high morbidity profound effects on the quality life patients their families. Drug-refractory seizures are hallmark treatment further complicated its morbidities, which evolve over patient's lifetime. This review provides comprehensive overview current future options for LGS. Six treatments specifically indicated as adjunct therapies LGS in US: lamotrigine, clobazam, rufinamide, topiramate, felbamate most recently cannabidiol. These have demonstrated reductions drop 15%-68% across trials, responder rates (≥ 50% reduction seizures) 37%-78%. Valproate still preferred first-line treatment, generally combination lamotrigine or clobazam. Other frequently used off-label include broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide perampanel, while recent evidence from observational studies has newer AED, levetiracetam analogue brivaracetam, may be effective well tolerated patients. clinical development fenfluramine late phase III, soticlestat-OV953/TAK-953, carisbamate ganaxolone. Non-pharmacologic interventions ketogenic diet, vagus nerve stimulation surgical interventions; these also expanding, potential less invasive techniques corpus callosotomy promise reducing complications. However, despite advancements, continue to experience significant burden. Because not entity, tailoring needed opposed 'one size fits all' approach. Further research into underlying aetiologies pathophysiology LGS, together advancements encompass this complex syndrome.

Language: Английский

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Cannabidiol in the treatment of epilepsy: Current evidence and perspectives for further research

Neuropharmacology, Journal Year: 2021, Volume and Issue: 185, P. 108442 - 108442

Published: Jan. 13, 2021

Language: Английский

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