Category Archives: Lennox-Gastaut

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

European drug agency approves cannabis-based medicine for severe forms of epilepsy

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“The European Medicines Agency (EMA) has approved the first cannabis based medicine to treat two rare and severe forms of childhood onset epilepsy, although hurdles remain before the drug becomes available on the NHS.”

https://www.bmj.com/content/366/bmj.l5708.full

Cannabis-based treatments as an alternative remedy for epilepsy

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Integrative Medicine Research“Much of the initial reports for cannabis use in seizure control centered on the compound 9-Δ-tetrahydrocannabinol (THC). However, due to the psychoactive properties of THC potential utility was somewhat limited and recent research has focused on non-psychoactive compounds such as cannabidiol (CBD).

The anti-seizure effects of CBD may come from mechanisms such as functional agonism or antagonism at several 7-transmembrane receptors, ion channels, and neurotransmitter transporters.

Recently, another compound that also is without psychoactive effects known as CBDV has also shown anti-seizure properties both in vivo and in vitro.

Many reports exist on illicit cannabis use through the smoking of marijuana by patients as a self-treatment.

Cannabis and cannabis-based treatments offer promising alternatives to traditional antiepileptic drugs (AEDs).

Due to the unfortunate fact that many patients suffer from Drug-resistant epilepsy (DRE), cannabis-based treatments have great value.

Cannabis-based treatments offer some patients with DRE a great remedy for their condition with limited side effects.

This option may prevent some patients with DRE from needing to consider more invasive options such as surgical interventions. In case studies, open label studies, and RCTs, one can see drastic improvements in the frequency of seizures in patients with certain forms of epilepsy.

It is imperative to continue research into cannabis as a potential primary treatment for epilepsy, particularly those with DRE, to help improve quality of life for millions of people suffering from epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/31463193

https://www.sciencedirect.com/science/article/pii/S221342201930157X?via%3Dihub

The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study.

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“Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time.

RESULTS:

Sixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p<0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders’ rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved.

CONCLUSIONS:

PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.”

https://www.ncbi.nlm.nih.gov/pubmed/31394352

https://www.epilepsybehavior.com/article/S1525-5050(19)30305-1/fulltext

Cannabis and Epilepsy.

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 Publication Cover“In recent years, the use of cannabidiol in the treatment of refractory epilepsy has been increasingly investigated and has been gaining public support as a novel way to treat these disorders.

Marijuana has been used for medical purposes for thousands of years, and a lot of research has been conducted over the last several decades into the chemistry and pharmacology of marijuana and its many compounds, including cannabidiol.

There are historical and recent scientific developments that support the use of cannabidiol in rare severe epilepsy syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/31385740

https://www.tandfonline.com/doi/abs/10.1080/15504263.2019.1645372?journalCode=wjdd20

Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy.

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 “Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties.

During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy.

In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal.

In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS.

Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex.

The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances.

About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.”

https://www.ncbi.nlm.nih.gov/pubmed/31372958

https://link.springer.com/article/10.1007%2Fs40265-019-01171-4

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study.

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 Image result for frontiers in neurology“There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy.

We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study.

Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified.

Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication.

Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.”

https://www.ncbi.nlm.nih.gov/pubmed/31333569

https://www.frontiersin.org/articles/10.3389/fneur.2019.00716/full

Cognitive functioning following long-term cannabidiol use in adults with treatment-resistant epilepsy.

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“Cognitive dysfunction is a common comorbidity in adults with treatment-resistant epilepsy (TRE).

Recently, cannabidiol (CBD) has demonstrated efficacy in epilepsy treatment. However, our understanding of CBD’s cognitive effects in epilepsy is limited.

We examined long-term cognitive effects of CBD in adults with TRE as part of an ongoing prospective, open-label safety study.

Longitudinal analysis revealed no significant group change across the two global composite scales. Of the seven individual cognitive tests, none changed significantly over time. No correlation was found between the cognitive change scores and CBD dose (all P’s ≥; 0.2). Change in cognitive test performance was not associated change in seizure severity rating.

These findings are encouraging and indicate that long-term administration of pharmaceutical grade CBD is overall cognitively well-tolerated in adults with TRE.”

https://www.ncbi.nlm.nih.gov/pubmed/31220785

https://www.epilepsybehavior.com/article/S1525-5050(18)30931-4/fulltext

Purified Cannabidiol for Treatment of Refractory Epilepsies in Pediatric Patients with Developmental and Epileptic Encephalopathy.

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“A pharmaceutical grade formulation of cannabidiol (CBD) has been approved for the treatment of Dravet syndrome and Lennox-Gastaut syndrome; however, this formulation is not yet available to patients outside the USA. In addition, CBD is thought to have broad anti-seizure properties that may be beneficial for other types of intractable epilepsy.

OBJECTIVE:

The aim of this study was to evaluate the efficacy, safety and tolerability of artisanal medical CBD oil in patients with developmental and epileptic encephalopathy (DEE) at the tertiary epilepsy center of Bambino Gesù Children’s Hospital in Rome, Italy.

RESULTS:

Twenty-nine patients were enrolled in this study (41.4% male). The mean duration of exposure to artisanal CBD was 11.2 months [range 6-25 months; standard deviation (SD) ± 4.4 months]. Mean age at study enrollment was 9.3 years (range 1.9-16.3 years; SD ± 4.7 years). Eleven out of 29 patients (37.9%) had a ≥ 50% improvement in seizure frequency; one patient became seizure free. None of the patients reported worsening seizure frequency; however, 18 patients (62.1%) experienced no beneficial effect regarding seizure frequency. Adverse effects were reported in seven patients (24.14%), most commonly somnolence, decreased appetite and diarrhea. Adverse events were mild and transient, and no dose modification of CBD or other AEDs was required.

CONCLUSIONS:

These data suggest that CBD may have beneficial effects in patients with DEE and an acceptable safety profile. Placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in patients with DEE.”

 https://www.ncbi.nlm.nih.gov/pubmed/31179531
https://link.springer.com/article/10.1007%2Fs40272-019-00341-x

Medical Marijuana in the Pediatric Population With Epilepsy—What You Should Know

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Journal of Pediatric Health Care Home

“This article discusses the controversial but promising topic of medical marijuana (MM) use in the pediatric population with epilepsy. Included is the importance of MM throughout history, the pharmacodynamics and pharmacokinetics, and a literature review that provides anecdotal evidence of the positive effect MM has on children suffering from seizures. From this literature review, dosage for treatment and management is provided. Also discussed is the recent FDA-approved pharmaceutical grade CBD product, Epidiolex, for treatment of two pediatric-onset seizure syndromes, Lennox-Gastaut and Dravet. Clinical implications regarding adverse side effects of MM use are also discussed. The aim of this article is to arm providers with contemporary knowledge on the risks and benefits of MM use in the pediatric population with epilepsy, which may boost their skills and confidence in educating and advocating for children with seizures. This novel, ever-changing medication is in the forefront of history and the news, making this topic especially important for review.”

 https://www.jpedhc.org/article/S0891-5245(18)30699-0/fulltext