Category Archives: Epilepsy

Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology.

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Clinical Pharmacology in Drug Development

“Cannabidiol (CBD) is the main nonpsychoactive component of the cannabis plant. It has been associated with antiseizure, antioxidant, neuroprotective, anxiolytic, anti-inflammatory, antidepressant, and antipsychotic effects.

PTL101 is an oral gelatin matrix pellets technology-based formulation containing highly purified CBD embedded in seamless gelatin matrix beadlets. Study objectives were to evaluate the safety and tolerability of PTL101 containing 10 and 100 mg CBD, following single administrations to healthy volunteers and to compare the pharmacokinetic profiles and relative bioavailability of CBD with Sativex oromucosal spray (the reference product) in a randomized, crossover study design.

Administration of PTL101 containing 10 CBD, led to a 1.7-fold higher Cmax and 1.3-fold higher AUC compared with the oromucosal spray. Tmax following both modes of delivery was 3-3.5 hours postdosing. CBD exhibited about a 1-hour lag in absorption when delivered via PTL101. A 10-fold increase in the dose resulted in an ∼15-fold increase in Cmax and AUC. Bioavailability of CBD in the 10-mg PTL101 dose was 134% relative to the reference spray.

PTL101 is a pharmaceutical-grade, user-friendly oral formulation that demonstrated safe and efficient delivery of CBD and therefore could be an attractive candidate for therapeutic indications.”

https://www.ncbi.nlm.nih.gov/pubmed/29125702

http://onlinelibrary.wiley.com/doi/10.1002/cpdd.408/abstract

Efficacy and safety of cannabis for treating children with refractory epilepsy.

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Nursing Children and Young People

“The aim of this literature review was to examine the evidence base for the safety and efficacy of cannabis in treating children with refractory epilepsy. Clinical and medical databases were searched and four articles were included in the final analysis, which included retrospective reviews and open-label trials with a total sample size of 424. One clinical trial included administration of cannabidiol, the non-psychoactive compound of cannabis, while the other three articles stated that the compound administered to participants contained tetrahydrocannabidiol, the psychoactive constituent of cannabis.

Cannabis may reduce seizures in some children and young people with refractory epilepsy, however, its success may be affected by aetiology of the epilepsy or concomitant anti-epileptic drug use, and a therapeutic dose has not been found. Positive side effects were also found including improved sleep, alertness and mood. More research is needed on this subject, including randomised controlled trials. Nurses who are aware of patients and families wishing to trial cannabis for refractory epilepsy should have full and frank discussions.”

https://www.ncbi.nlm.nih.gov/pubmed/29115760

https://journals.rcni.com/nursing-children-and-young-people/efficacy-and-safety-of-cannabis-for-treating-children-with-refractory-epilepsy-ncyp.2017.e907

Cannabinoid receptor 1/2 double-knockout mice develop epilepsy.

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Epilepsia

“The endocannabinoid system has gained attention as an important modulator of activity in the central nervous system. Initial studies focused on cannabinoid receptor 1 (CB1), which is widely expressed in the brain, but recent work also implicates cannabinoidreceptor 2 (CB2) in modulating neuronal activity.

Both receptors are capable of reducing neuronal activity, generating interest in cannabinoid receptor agonists as potential anticonvulsants.

CB1 (Cnr1) and CB2 (Cnr2) single-knockout mice have been generated, with the former showing heightened seizure sensitivity, but not overt seizures. Given overlapping and complementary functions of CB1 and CB2 receptors, we queried whether double-knockout mice would show an exacerbated neurological phenotype.

Strikingly, 30% of double-knockout mice exhibited provoked behavioral seizures, and 80% were found to be epileptic following 24/7 video-electroencephalographic monitoring. Single-knockout animals did not exhibit seizures. These findings highlight the importance of the endocannabinoid system for maintaining network stability.”

https://www.ncbi.nlm.nih.gov/pubmed/29105060

http://onlinelibrary.wiley.com/doi/10.1111/epi.13930/abstract

The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy.

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 Publication Cover

“Epilepsy, commonly encountered by patients with brain tumors, is often refractory to standard therapies. Our aim was to examine the safety and efficacy of pharmaceutical grade cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) in those patients with epilepsy with concomitant tumors enrolled in The University of Alabama at Birmingham CBD Program (NCT02700412 and NCT02695537). Of the three patients with refractory seizures and a history of a primary brain tumor, two had improvement in seizure frequency and all three had improvement in seizure severity. These pilot results suggest that CBD should be further studied for the treatment of brain tumor-related epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/29063814

http://www.tandfonline.com/doi/abs/10.1080/13554794.2017.1391294?journalCode=nncs20

Medical Cannabinoids in Children and Adolescents: A Systematic Review

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AAP Gateway

“CONTEXT: Legalization of medical marijuana in many states has led to a widening gap between the accessibility and the evidence for cannabinoids as a medical treatment.

OBJECTIVE: To systematically review published reports to identify the evidence base of cannabinoids as a medical treatment in children and adolescents.

RESULTS: Evidence for benefit was strongest for chemotherapy-induced nausea and vomiting, with increasing evidence of benefit for epilepsy.”  http://pediatrics.aappublications.org/content/early/2017/10/19/peds.2017-1818

“Limited data on medical cannabis use in children. Strongest evidence supports use to reduce seizures, side effects of chemotherapy.”  https://www.sciencedaily.com/releases/2017/10/171023094606.htm

“Marijuana Can Help Children with Seizures, Cancer Nausea”   https://www.healthline.com/health-news/marijuana-can-help-children-with-seizures-cancer-nausea

“Medical Marijuana Reduces CINV, Seizures in Children”  https://www.medscape.com/viewarticle/887616

The Role of BK Channels in Antiseizure Action of the CB1 Receptor Agonist ACEA in Maximal Electroshock and Pentylenetetrazole Models of Seizure in Mice.

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“The anticonvulsant effect of cannabinoid compound has been shown in various models of seizure. On the other hand, there are controversial findings about the role of large conductance calcium-activated potassium (BK) channels in the pathogenesis of epilepsy. Also, there is no data regarding the effect of co-administration of cannabinoid type 1 (CB1) receptor agonists and BK channels antagonists in the acute models of seizure in mice.

In this study, the effect of arachidonyl-2′-chloroethylamide (ACEA), a CB1 receptor agonist, and a BK channel antagonist, paxilline, either alone or in combination was investigated.

Both pentylenetetrazole (PTZ) and maximal electroshock (MES) acute models of seizure were used to evaluate the protective effects of drugs. Mice were randomly selected in different groups: (i) control group; (ii) groups that received different doses of either paxilline or ACEA; and (iii) groups that received combinations of ACEA and paxillin at different doses. In MES model, prevention of hindlimb tonic extension (HLTE) was considered as protective effect. In PTZ model, the required dose of PTZ (mg/kg) to induce tonic-clonic seizure with loss of righting reflex was considered as seizure threshold. In PTZ model, while administration of ACEA per se (5 and 10 mg/kg) caused protective effect against seizure; however, co-administration of ACEA and ineffective doses of paxilline attenuated the antiseizure effects of paxilline. In MES model, while pretreatment by ACEA showed protective effects against seizure; however, co-administration of paxilline and ACEA caused an antagonistic interaction for their antiseizure properties.

Our results showed a protective effect of ACEA in both PTZ and MES acute models of seizure. This effect was attenuated by co-administration with paxilline, suggesting the involvement of BK channels in antiseizure activity of ACEA.”

https://www.ncbi.nlm.nih.gov/pubmed/28979317

Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome.

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Current Issue

“Worldwide medicinal use of cannabis is rapidly escalating, despite limited evidence of its efficacy from preclinical and clinical studies. Here we show that cannabidiol (CBD) effectively reduced seizures and autistic-like social deficits in a well-validated mouse genetic model of Dravet syndrome (DS), a severe childhood epilepsy disorder caused by loss-of-function mutations in the brain voltage-gated sodium channel NaV1.1.

The duration and severity of thermally induced seizures and the frequency of spontaneous seizures were substantially decreased. Treatment with lower doses of CBD also improved autistic-like social interaction deficits in DS mice.

Phenotypic rescue was associated with restoration of the excitability of inhibitory interneurons in the hippocampal dentate gyrus, an important area for seizure propagation. Reduced excitability of dentate granule neurons in response to strong depolarizing stimuli was also observed.

The beneficial effects of CBD on inhibitory neurotransmission were mimicked and occluded by an antagonist of GPR55, suggesting that therapeutic effects of CBD are mediated through this lipid-activated G protein-coupled receptor.

Our results provide critical preclinical evidence supporting treatment of epilepsy and autistic-like behaviors linked to DS with CBD. We also introduce antagonism of GPR55 as a potential therapeutic approach by illustrating its beneficial effects in DS mice.

Our study provides essential preclinical evidence needed to build a sound scientific basis for increased medicinal use of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/28973916

http://www.pnas.org/content/early/2017/09/26/1711351114

Cannabidiol reduced frequency of convulsive seizures in drug resistant Dravet syndrome.

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BMJ Journals

“Study design

Design: Multinational double-blinded placebo-controlled trial. Patients randomised in 1:1 ratio to receive cannabidiol or placebo, in addition to stable antiepileptic treatment regime.

Study question

Setting: Twenty-three centres in Europe and USA.

 Patients: Patients aged 2 years to 18 years with established diagnosis of Dravet syndrome having at least four convulsive seizures during the 28-day baseline period despite regular antiepileptic medication.

Intervention: Adjunctive cannabidiol or placebo oral solution at 20 mg per kilogram of body weight per day.

Primary outcome: Percentage change in median frequency of convulsive seizures per month.

Follow-up period: Outcome measured over a 14-week treatment period in comparison to a 4-week baseline period.

Patient follow-up: One hundred and eight (90%) completed the trial: 85% (52/61) in the cannabidiol group and …”

http://ep.bmj.com/content/early/2017/09/22/archdischild-2017-313700

The FAAH inhibitor URB597 suppresses hippocampal maximal dentate afterdischarges and restores seizure-induced impairment of short and long-term synaptic plasticity.

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“Synthetic cannabinoids and phytocannabinoids have been shown to suppress seizures both in humans and experimental models of epilepsy.

However, they generally have a detrimental effect on memory and memory-related processes. Here we compared the effect of the inhibition of the endocannabinoid (eCB) degradation versus synthetic CB agonist on limbic seizures induced by maximal dentate activation (MDA) acute kindling. Moreover, we investigated the dentate gyrus (DG) granule cell reactivity and synaptic plasticity in naïve and in MDA-kindled anaesthetised rats.

We found that both the fatty acid amide hydrolase (FAAH) inhibitor URB597 and the synthetic cannabinoid agonist WIN55,212-2 displayed AM251-sensitive anti-seizure effects. WIN55,212-2, dose-dependently (0.5-2 mg/kg, i.p.) impaired short-term plasticity (STP) and long-term potentiation (LTP) at perforant path-DG synapses in naïve rats. Strikingly, URB597 (1 mg/kg, i.p.) was devoid of any deleterious effects in normal conditions, while it prevented seizure-induced alterations of both STP and LTP.

Our evidence indicates that boosting the eCB tone rather than general CB1 activation might represent a potential strategy for the development of a new class of drugs for treatment of both seizures and comorbid memory impairments associated with epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/28894217

https://www.nature.com/articles/s41598-017-11606-1

[Cannabis use in Epilepsy. Current situation in Argentina and abroad].

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“Although at present we have over 20 different types of drugs for epilepsy, 30 to 40% of patients continue to have seizures.

Preliminary data from human studies suggest that cannabis, cannabidiol in particular, is effective in the treatment of some patients with epilepsy.

However, the available data are limited and do not allow defnitive conclusions. Only randomized clinical trials with controlled double-blind, placebo-controlled utilizing secure preparations and one or more cannabinoids, will provide comprehensive information on the effcacy and safety of use.

In order to perform these trials it is necessary to have legislation authorizing the use of cannabis on epilepsy.”

 https://www.ncbi.nlm.nih.gov/pubmed/28898306