Category Archives: Epilepsy

Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967.

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ijms-logo “Many epilepsy patients are refractory to conventional antiepileptic drugs.

Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations.

Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy.

This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels.

We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents.

Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/32244818

https://www.mdpi.com/1422-0067/21/7/2454

Cannabidiol in treatment of refractory epileptic spasms: An open-label study.

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Cover image volume 104, Issue “This study aimed to evaluate clinical efficacy and safety of purified pharmaceutical cannabidiol (CBD) as an adjunctive therapy in refractory childhood-onset epileptic spasms (ES).

METHODS:

Nine patients with ES were enrolled in an Institutional Review Board (IRB)- and Food and Drug Administration (FDA)-approved expanded access investigational new drug trial. Patients received plant-derived highly purified CBD in oral solution in addition to their baseline medications at an initial dosage of 5 mg/kg/day, which was increased by 5 mg/kg/day every week to an initial target dosage of 25 mg/kg/day. Seizure frequency, adverse event, and parents’ subjective reports of cognitive and behavioral changes were recorded after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment. Responder rates (percent of patients with >50% reduction in ES frequency from baseline) were calculated. Electrographic changes were studied in relation to CBD initiation and clinical response.

RESULTS:

Overall, the responder rates in 9 patients were 67%, 78%, 67%, 56%, 78%, 78%, and 78% after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment, respectively. Three out of nine patients (33%) were ES free after two months of treatment. Parents reported subjective improvements in cognitive and behavioral domains. Side effects, primarily drowsiness, were seen in 89% of patients (n = 8). Eight of the nine (89%) patients had electroencephalographic (EEG) studies prior to and after initiation of CBD. Three out of five patients (60%) had resolution in their hypsarrhythmia pattern.

SIGNIFICANCE:

Purified pharmaceutical CBD may be an effective and safe adjunctive therapy in refractory ES and may also be associated with improvements in electrographic findings.”

https://www.ncbi.nlm.nih.gov/pubmed/32169600

“Purified pharmaceutical cannabidiol seems an effective adjunctive therapy in refractory epileptic spasms. Purified pharmaceutical cannabidiol has corresponding electrographic changes. Purified pharmaceutical cannabidiol seems to exhibit acceptable safety profile.”

https://linkinghub.elsevier.com/retrieve/pii/S1525505020301633

Is cannabidiol a drug acting on unconventional targets to control drug-resistant epilepsy?

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Publication cover image“Cannabis has been considered as a therapeutic strategy to control intractable epilepsy.

Several cannabis components, especially cannabidiol (CBD), induce antiseizure effects. However, additional information is necessary to identify the types of epilepsies that can be controlled by these components and the mechanisms involved in these effects.

This review presents a summary of the discussion carried out during the 2nd Latin American Workshop on Neurobiology of Epilepsy entitled “Cannabinoid and epilepsy: myths and realities.” This event was carried out during the 10th Latin American Epilepsy Congress in San José de Costa Rica (September 28, 2018).

The review focuses to discuss the use of CBD as a new therapeutic strategy to control drug-resistant epilepsy. It also indicates the necessity to consider the evaluation of unconventional targets such as P-glycoprotein, to explain the effects of CBD in drug-resistant epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/32140642

“Cannabidiol is a multitarget drug that represents a new hope to control drug‐resistant epilepsy.”

https://onlinelibrary.wiley.com/doi/full/10.1002/epi4.12376

Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial.

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Image result for jama neurology“Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose.

OBJECTIVE:

To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome.

MAIN OUTCOMES AND MEASURES:

The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score.

RESULTS:

Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium.

CONCLUSIONS AND RELEVANCE:

Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety.”

https://www.ncbi.nlm.nih.gov/pubmed/32119035

https://jamanetwork.com/journals/jamaneurology/fullarticle/2762458

Overview of cannabidiol (CBD) and its analogues: Structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer’s disease.

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European Journal of Medicinal Chemistry“Herein, 11 general types of natural cannabinoids from Cannabis sativa as well as 50 (-)-CBD analogues with therapeutic potential were described. The underlying molecular mechanisms of CBD as a therapeutic candidate for epilepsy and neurodegenerative diseases were comprehensively clarified. CBD indirectly acts as an endogenous cannabinoid receptor agonist to exert its neuroprotective effects. CBD also promotes neuroprotection through different signal transduction pathways mediated indirectly by cannabinoid receptors. Furthermore, CBD prevents the glycogen synthase kinase 3β (GSK-3β) hyperphosphorylation caused by Aβ and may be developed as a new therapeutic candidate for Alzheimer’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/32109623

“For AD treatment, CBD can rescue the production of neurofibrillary tangles and inhibit neuronal apoptosis.”

https://www.sciencedirect.com/science/article/abs/pii/S0223523420301306?via%3DihubImage 1

Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects.

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“Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fat-containing meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits.

A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebo-controlled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses.

Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/32103958

https://www.dovepress.com/cannabinoids-in-the-treatment-of-epilepsy-current-status-and-future-pr-peer-reviewed-article-NDT

Application of Cannabinoids in Neurosciences: Considerations and Implications.

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 Current Issue Cover Image“Medicinal cannabinoid use continues to evolve across the United States, although legitimate federal recognition for medicinal purpose is lacking. Variability exists across states within the United States with respect to legislation, and health care institutions encounter challenges when patients present with a history of medicinal cannabinoid use. Emerging evidence in the field of neurosciences suggests a role of cannabinoids for neurologic medical conditions such as Parkinson disease, multiple sclerosis, and epilepsy. We aim to provide an overview of cannabinoids including a historical perspective, pharmacology, applications in neurosciences, and challenges in health care and academia. Knowledge of the appropriate role of cannabinoids in the clinical setting is essential for all health care practitioners including nursing.”

https://www.ncbi.nlm.nih.gov/pubmed/32084064

https://journals.lww.com/ccnq/Abstract/2020/04000/Application_of_Cannabinoids_in_Neurosciences_.9.aspx

Epilepsy and cannabidiol: a guide to treatment.

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 Image result for Epileptic Disord. journal“The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries.

Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome.

However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness.

This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/32096470

Possible therapeutic applications of cannabis in the neuropsychopharmacology field.

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European Neuropsychopharmacology“Cannabis use induces a plethora of actions on the CNS via its active chemical ingredients, the so-called phytocannabinoids.

These compounds have been frequently associated with the intoxicating properties of cannabis preparations. However, not all phytocannabinoids are psychotropic, and, irrespective of whether they are psychotropic or not, they have also shown numerous therapeutic properties.

These properties are mostly associated with their ability to modulate the activity of an intercellular communication system, the so-called endocannabinoid system, which is highly active in the CNS and has been found altered in many neurological disorders.

Specifically, this includes the neuropsychopharmacology field, with diseases such as schizophrenia and related psychoses, anxiety-related disorders, mood disorders, addiction, sleep disorders, post-traumatic stress disorder, anorexia nervosa and other feeding-related disorders, dementia, epileptic syndromes, as well as autism, fragile X syndrome and other neurodevelopment-related disorders.

Here, we gather, from a pharmacological and biochemical standpoint, the recent advances in the study of the therapeutic relevance of the endocannabinoid system in the CNS, with especial emphasis on the neuropsychopharmacology field. We also illustrate the efforts that are currently being made to investigate at the clinical level the potential therapeutic benefits derived from elevating or inhibiting endocannabinoid signaling in animal models of neuropsychiatric disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32057592

https://www.sciencedirect.com/science/article/abs/pii/S0924977X20300365?via%3Dihub

The proposed mechanisms of action of CBD in epilepsy.

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Image result for epileptic disorders journal“Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States and as EPIDYOLEX from the EU agency) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy. Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).”

 https://www.ncbi.nlm.nih.gov/pubmed/32053110
https://www.jle.com/fr/revues/epd/e-docs/the_proposed_mechanisms_of_action_of_cbd_in_epilepsy_316095/article.phtml