Category Archives: Lennox-Gastaut

Efficacy and Tolerance of Synthetic Cannabidiol for Treatment of Drug Resistant Epilepsy.

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Image result for frontiers in neurology“Controlled and open label trials have demonstrated efficacy of cannabidiol for certain epileptic encephalopathies.

However, plant derived cannabidiol products have been used almost exclusively. Efficacy of synthetically derived cannabidiol has not been studied before.

The objective of this study was to evaluate tolerability and efficacy of synthetic cannabidiol in patients with pharmacoresistant epilepsy.

Efficacy and tolerance in our study of synthetic CBD treatment in pharmacoresistant epilepsy is similar to open label studies using plant derived CBD.

Regarding economic and ecological aspects, synthetic cannabidiol might be a reasonable alternative to plant derived cannabidiol.”

https://www.ncbi.nlm.nih.gov/pubmed/31920934

“Over the last decade, the therapeutic use of cannabidiol (CBD) in intractable epilepsies has increased considerably. Its anticonvulsant properties have been shown in several animal models for acute and chronic epilepsy.

Recent randomized, controlled trials have demonstrated that CBD is superior to placebo in seizure reduction in children with Dravet syndrome and patients with Lennox-Gastaut syndrome. In addition, open label studies indicate that cannabidiol has anticonvulsive properties in a broader range of epilepsy syndromes and etiologies.

In summary, the results of this study provide class III evidence of efficacy and safety of synthetic cannabidiol in children and adults with pharmacoresistant epilepsy. Additional studies investigating efficacy and tolerance of synthetic CBD in larger cohorts are needed.”

https://www.frontiersin.org/articles/10.3389/fneur.2019.01313/full

Exploiting cannabinoid and vanilloid mechanisms for epilepsy treatment.

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“This review focuses on the possible roles of phytocannabinoids, synthetic cannabinoids, endocannabinoids, and “transient receptor potential cation channel, subfamily V, member 1” (TRPV1) channel blockers in epilepsy treatment.

The phytocannabinoids are compounds produced by the herb Cannabis sativa, from which Δ9-tetrahydrocannabinol (Δ9-THC) is the main active compound. The therapeutic applications of Δ9-THC are limited, whereas cannabidiol (CBD), another phytocannabinoid, induces antiepileptic effects in experimental animals and in patients with refractory epilepsies.

Synthetic CB1 agonists induce mixed effects, which hamper their therapeutic applications. A more promising strategy focuses on compounds that increase the brain levels of anandamide, an endocannabinoid produced on-demand to counteract hyperexcitability. Thus, anandamide hydrolysis inhibitors might represent a future class of antiepileptic drugs. Finally, compounds that block the TRPV1 (“vanilloid”) channel, a possible anandamide target in the brain, have also been investigated.

In conclusion, the therapeutic use of phytocannabinoids (CBD) is already in practice, although its mechanisms of action remain unclear. Endocannabinoid and TRPV1 mechanisms warrant further basic studies to support their potential clinical applications.”

https://www.ncbi.nlm.nih.gov/pubmed/31839498

“Cannabidiol is in clinical use for refractory epilepsies.”

https://www.epilepsybehavior.com/article/S1525-5050(19)30373-7/fulltext

The use of medical grade cannabis in Italy for drug-resistant epilepsy: a case series.

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 “In Italy, medical grade cannabis (MGC) can be prescribed for different medical conditions, including drug-resistant epilepsy (DRE), once standard and approved therapies have failed, or caused non-tolerable side effects.

Here, we present a retrospective case series report of five patients with DRE who started therapy with MGC. Authorized ISO 9001:2008 pharmacies prepared MGC according to Italian laws. Olive oil extracts (OOEs) were prepared following standard extraction protocols, and cannabinoids were measured on each OOE to check for successful extraction.

After treatment with MGC, all patients reported a reduction in seizure frequency and severity, and some reported improved mood, sleep quality, and general well-being without relevant side effects.

Despite the small sample size and open-label nature of the data, we show that MGC may be successfully used to treat DRE. This is especially true when considering that no valid therapeutic option exists for these patients and that MGC was extremely well tolerated.”

https://www.ncbi.nlm.nih.gov/pubmed/31776867

https://link.springer.com/article/10.1007%2Fs10072-019-04162-1

Cannabinoids for drug-resistant seizures in a critically ill patient-Case report and literature review.

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Publication cover image“Drug-resistant seizures are life-threatening and contribute to sustained hospitalization.

We present the case of a critically ill 28-year-old male with Lennox-Gastaut syndrome who had approximately 30 seizures/day in the intensive care unit.

CASE DESCRIPTION:

Patient required mechanical ventilation and pharmacologically induced thiopentone coma.

He was commenced on cannabidiol and subsequently extubated.

He remained seizure-free thereafter on a combination of cannabidiol and anti-epileptic medication that predated his critical illness.

WHAT IS NEW AND CONCLUSION:

Our case report provides a unique perspective on the role of cannabidiol in achieving remission from drug-resistant seizures in critically ill patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31770462

https://onlinelibrary.wiley.com/doi/abs/10.1111/jcpt.13082

Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice.

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Publication cover image“The endocannabinoid system (ECS) is comprised of cannabinoid receptors 1 and 2 (CB1R and CB2R), endogenous ligands, and regulatory enzymes, and serves to regulate several important physiological functions throughout the brain and body.

Recent evidence suggests that the ECS may be a promising target for the treatment of epilepsy, including epilepsy subtypes that arise from mutations in the voltage-gated sodium channel SCN1A.

The objective of this study was to explore the effects of modulating CB2R activity on seizure susceptibility.

Our results demonstrate that reduced CB2R activity is associated with increased seizure susceptibility. CB2Rs might therefore provide a therapeutic target for the treatment of some forms of epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/31758544

https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.16388

Cannabis Influences the Putative Cytokines-Related Pathway of Epilepsy among Egyptian Epileptic Patients.

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brainsci-logo“The study aims to investigate: (1) the prevalence of cannabis among epileptic patients seen at Mansoura University Hospital, (2) serum levels and gene expression of cytokines in epilepsy patients and the controls. and (3) the possibility that cannabis use affects the cytokine levels in epilepsy patients, triggering its future use in treatment.

We recruited 440 epilepsy patients and 200 controls matched for age, gender, and ethnicity. Of the epileptic patients, 37.5% demonstrated lifetime cannabis use with a mean duration of 15 ± 73 years. Serum levels of interleukin IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α), were analyzed and gene expression analysis was conducted only for those cytokines that were different between groups in the serum analysis.

The “Epilepsy-only” patients had significantly higher serum and mRNA levels of IL-1α, β, IL-2,6,8, and TNF-α compared to the controls and the “Cannabis+Epilepsy” group (p = 0.0001). IL-10 showed significantly lower levels in the “Epilepsy-only” patients compared to the controls and “Cannabis+Epilepsy” (p = 0.0001). Cannabis use is prevalent among epilepsy patients.

Epilepsy is characterized by a pro-inflammatory state supported by high serum and gene expression levels.

Cannabis users demonstrated significantly lower levels of inflammatory cytokines compared to epilepsy non-cannabis users which might contribute to its use in the treatment of resistant epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/31757102

https://www.mdpi.com/2076-3425/9/12/332

Efficacy and adverse event profile of cannabidiol and medicinal cannabis for treatment-resistant epilepsy: Systematic review and meta-analysis.

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“This paper aimed to systematically examine the efficacy and adverse event (AE) profile of cannabidiol and medicinal cannabis by analyzing qualitative and meta-analytic data.

According to the results, a statistically meaningful effect of cannabidiol compared with placebo was observed (p < 0.00001). When comparing treatment with cannabidiol or medicinal cannabis, significance was not found for the AE profile (p = 0.74). As AEs for cannabidiol were more common under short-term than under long-term treatment (p < 0.00001), this approach was favorable in the long term.

Furthermore, cannabidiol is more effective than placebo, regardless of the etiology of epileptic syndromes and dosage.

Overall, the AE profile did not differ across treatments with cannabidiol or medicinal cannabis, though it did differ favorably for long-term than for short-term treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31731110

“CBD treatments were effective compared with placebo, regardless of the dose administered. •The safety analysis is related to tolerable SEs found in studies with both CBD and medicinal CNB. •There was a greater tendency for adverse events in short-term treatment compared with long-term treatment.”

https://www.epilepsybehavior.com/article/S1525-5050(19)30862-5/fulltext

NICE recommends cannabis based drugs for epilepsy and multiple sclerosis

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Image result for the bmj journal“In final appraisal documents the UK National Institute for Health and Care Excellence has recommended the use of cannabidiol with clobazam for treating seizures associated with two rare and severe forms of epilepsy: Lennox-Gastaut syndrome and Dravet syndrome.

The decision comes after NICE initially rejected the use of cannabidiol in draft appraisal documents released in August because of concerns over a lack of data on the drug’s long term effectiveness.

However, in its latest documents NICE has recommended the drug for people aged 2 or over, reporting that clinical trials had shown that, in comparison with usual care, cannabidiol reduced the number of drop and non-drop seizures and the number of convulsive and non-convulsive seizures.

The final appraisal documents are out for consultation until 27 November, and final approval is expected on 18 December.

The documents were released alongside NICE’s final guideline on cannabis based medicinal products. In this, NICE also recommends the use of nabiximols for patients with multiple sclerosis.”

https://www.ncbi.nlm.nih.gov/pubmed/31712197

https://www.bmj.com/content/367/bmj.l6453

A new mechanism for Cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models.

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Publication cover image“EpidiolexTM , a form of highly purified cannabidiol (CBD) derived from Cannabis plants has demonstrated seizure control activity in patients with Dravet syndrome, without a fully-elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level.

We use a tractable biomedical model organism, Dictyostelium, to identify protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet Syndrome mouse model and an acute in vitro seizure model.

Key Results CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human GCSH protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis.

Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment. Conclusions and Implications

Our results suggest a novel mechanism for CBD in the regulating methionine levels, and identify altered one-carbon metabolism in Dravet syndrome and seizure activity.”

https://www.ncbi.nlm.nih.gov/pubmed/31693171

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14892

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.

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Epilepsia banner“Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam.

RESULTS:

CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation.

SIGNIFICANCE:

Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.”

https://www.ncbi.nlm.nih.gov/pubmed/31625159

“Our results here suggest a novel benefit of CBD and clobazam combination therapy on premature death, a devastating aspect of the Dravet syndrome phenotype.”

https://onlinelibrary.wiley.com/doi/full/10.1111/epi.16355