Category Archives: Epilepsia

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Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

Category : Epilepsia

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Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

Pharmacotherapy. 2016 Jul;36(7):781-96

Authors: Fasinu PS, Phillips S, ElSohly MA, Walker LA

Abstract
States and the federal government are under growing pressure to legalize the use of cannabis products for medical purposes in the United States. Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted ∆(9) -tetrahydrocannabinol (∆(9) -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader. This review provides an overview of the pharmacology and toxicology of CBD; summarizes some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and assesses the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States. Unlike Δ(9) -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors, whose activation results in the psychotropic effects characteristic of Δ(9) -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use. CBD exhibits neuroprotective, antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties. In combination with Δ(9) -THC, CBD has received regulatory approvals in several European countries and is currently under study in trials registered by the U.S. Food and Drug Administration in the United States. A number of states have passed legislation to allow for the use of CBD-rich, limited Δ(9) -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications. Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain.

PMID: 27285147 [PubMed – indexed for MEDLINE]

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

Category : Epilepsia

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

Vertex. 2016 Nov;XXVII(130):457-462

Authors: Kochen S

Abstract
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.

PMID: 28898306 [PubMed – in process]

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An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.

Category : Epilepsia

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An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.

Cannabis Cannabinoid Res. 2017;2(1):139-154

Authors: Iffland K, Grotenhermen F

Abstract
Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs. Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects. Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.

PMID: 28861514 [PubMed]

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The potential role of cannabinoids in epilepsy treatment.

Category : Epilepsia

The potential role of cannabinoids in epilepsy treatment.

Expert Rev Neurother. 2017 Aug 26;:

Authors: De Caro C, Leo A, Citraro R, De Sarro C, Russo R, Calignano A, Russo E

Abstract
INTRODUCTION: Epilepsy is one of the world’s oldest recognized and prevalent neurological diseases. It has a great negative impact on patients’ quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs’ side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention. Areas Covered: This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system. Expert commentary: Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy. On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy.

PMID: 28845714 [PubMed – as supplied by publisher]

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Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: Pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels.

Category : Epilepsia

Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: Pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels.

Epilepsy Behav. 2017 Aug 15;75:29-35

Authors: Vilela LR, Lima IV, Kunsch ÉB, Pinto HPP, de Miranda AS, Vieira ÉLM, de Oliveira ACP, Moraes MFD, Teixeira AL, Moreira FA

Abstract
Cannabidiol (CBD), the main nonpsychotomimetic compound from Cannabis sativa, inhibits experimental seizures in animal models and alleviates certain types of intractable epilepsies in patients. Its pharmacological profile, however, is still uncertain. Here we tested the hypothesis that CBD anticonvulsant mechanisms are prevented by cannabinoid (CB1 and CB2) and vanilloid (TRPV1) receptor blockers. We also investigated its effects on electroencephalographic (EEG) activity and hippocampal cytokines in the pentylenetetrazole (PTZ) model. Pretreatment with CBD (60mg/kg) attenuated seizures induced by intraperitoneal, subcutaneous, and intravenous PTZ administration in mice. The effects were reversed by CB1, CB2, and TRPV1 selective antagonists (AM251, AM630, and SB366791, respectively). Additionally, CBD delayed seizure sensitization resulting from repeated PTZ administration (kindling). This cannabinoid also prevented PTZ-induced EEG activity and interleukin-6 increase in prefrontal cortex. In conclusion, the robust anticonvulsant effects of CBD may result from multiple pharmacological mechanisms, including facilitation of endocannabinoid signaling and TRPV1 mechanisms. These findings advance our understanding on CBD inhibition of seizures, EEG activity, and cytokine actions, with potential implications for the development of new treatments for certain epileptic syndromes.

PMID: 28821005 [PubMed – as supplied by publisher]

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Antiepileptic drugs in clinical development: differentiate or die?

Category : Epilepsia

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Antiepileptic drugs in clinical development: differentiate or die?

Curr Pharm Des. 2017 Aug 09;:

Authors: Zaccara G, Schmidt D

Abstract
BACKGROUND: Animal models when carefully selected, designed and conducted, are important parts of any translational drug development strategy. However, research of new compounds for patients with drug-resistant epilepsies is still based on animal experiments, mostly in rodents, which are far from being a model of chronic human epilepsy and have failed to differentiate the efficacy of new compounds versus standard drug treatment. Objective The objective was identification and description of compounds in clinical development in 2016.
METHOD: Search was conducted from the website of the U.S. National Institutes of Health and from literature.
RESULTS: Identified compounds have been divided in two groups: 1) compounds initially developed for the treatment of diseases other than epilepsy: biperiden, bumetanide, everolimus, fenfluramine, melatonin, minocycline, verapamil. 2) Compounds specifically developed for the treatment of epilepsy: allopregnanolone, cannabidiol, cannabidivarin, ganaxolone, nalutozan, PF-06372865, UCB0942, and cenobamate. Everolimus, and perhaps, fenfluramine are effective in specific epileptic diseases and may be considered as true disease modifying antiepileptic drugs. These are tuberous sclerosis complex for everolimus and Dravet syndrome for fenfluramine. With the exception of a few other compounds such as cannabinidiol, cannabidivarin and minocycline, the vast majority of other compounds had mechanisms of action which are similar to the mechanism of action of the anti-seizure drugs already in the market.
CONCLUSION: Substantial improvements in the efficacy, specifically as pharmacological treatment of drug-resistant epilepsy is regarded, are not expected. New drugs should be developed to specifically target the biochemical alteration which characterizes the underlying disease and also include targets that contribute to epileptogenesis in relevant epilepsy models.

PMID: 28799516 [PubMed – as supplied by publisher]

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Safety profile of the newest antiepileptic drugs: a curated literature review.

Category : Epilepsia

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Safety profile of the newest antiepileptic drugs: a curated literature review.

Curr Pharm Des. 2017 Aug 09;:

Authors: Palleria C, Cozza G, Khengar R, Libri V, De Sarro G

Abstract
BACKGROUND: Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remain unsatisfactory. In addition, whilst several antiepileptic drugs (AEDs) have been approved and consequently marketed in recent years, little is known about their long-term safety and tolerability. Availability of the newest AEDs, characterized by improved pharmacokinetic profiles, has positively impacted the treatment approach for patients with partial seizures in clinical practice. However, the main cause of treatment failure is still poor patient compliance due to the occurrence of adverse drug reactions (ADRs) that lead to treatment withdrawal in about 25% of cases before achieving maximal efficacy, and is associated with increasing health care costs.
METHODS: In this Review, we conducted an online database search using Medline, PubMed, Embase, and the Cochrane Online Library to review the available studies highlighting the clinical relevance of side effects, pharmacological interactions, safety and tolerability of the newest AEDs: Brivaracetam (BRV), Cannabidiol (CBD), Eslicarbazepine acetate (ESL), Lacosamide (LCM), and Perampanel (PER).
RESULTS: The principal benefit of the newest AEDs, in addition to reduced frequency and seizure severity, is the low number and severity of ADRs reported compared to more historic drugs.
CONCLUSION: Early detection of ADRs could lead to an improvement in patients’ quality of life, therefore it is important to monitor ADRs and to adequately perform post marketing surveillance in the clinical practice setting.

PMID: 28799510 [PubMed – as supplied by publisher]

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Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid.

Category : Epilepsia

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Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid.

Int J Mol Sci. 2017 Jul 31;18(8):

Authors: Kozela E, Juknat A, Vogel Z

Abstract
The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection. The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies. The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.

PMID: 28788104 [PubMed – in process]

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Interactions between cannabidiol and commonly used antiepileptic drugs.

Category : Epilepsia

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Interactions between cannabidiol and commonly used antiepileptic drugs.

Epilepsia. 2017 Aug 06;:

Authors: Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP, UAB CBD Program

Abstract
OBJECTIVE: To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs.
METHODS: In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate.
RESULTS: Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01).
SIGNIFICANCE: Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.

PMID: 28782097 [PubMed – as supplied by publisher]

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Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy?

Category : Epilepsia

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Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy?

J Epilepsy Res. 2017 Jun;7(1):16-20

Authors: Koo CM, Kang HC

Abstract
Epilepsy is an important disease that affects brain function, particularly in those under 3 years old. Uncontrolled seizures can affect cognitive function and quality of life. For these reasons, many trials have been conducted to investigate treatments for pediatric epilepsy. Currently, many antiepileptic drugs are available for the treatment of epilepsy, but cases of intractable epilepsy continue to exist. In the past, cannabis has been tested as a potential treatment of intractable epilepsy. Since 2013, 10 epilepsy centers in America have conducted research regarding the efficacy of cannabis to treat epilepsy. Cannabis has many components, including cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC). THC has psychoactive properties exerted through its binding of the cannabinoid receptor (CBR) whereas CBD is a CBR antagonist. The inhibition of epilepsy by CBD may therefore be caused by various mechanisms, although the detailed mechanisms of CBD actions have not yet been well defined. In most studies, trial doses of CBD were 2-5 mg/kg/day. Several such studies have shown that CBD does have efficacy for treatment of epilepsy. Reported adverse effects of CBD were mostly mild, including drowsiness, diarrhea, and decreased appetite. Severe adverse reactions requiring treatment, such as status epilepticus, have also been reported but it is not clear that this is related to CBD. Furthermore, many previous studies have been limited by an open-label or survey design. In future, double-blind, controlled trials are required and the use of CBD to treat other neurological problems should also be investigated.

PMID: 28775950 [PubMed]

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