Investigational small molecules in phase II clinical trials for the treatment of epilepsy

Greco, Marco; Varriale, Gaia; Coppola, Giangennaro; Operto, Francesca Felicia; Verrotti, Alberto; Iezzi, Maria Laura

doi:10.1080/13543784.2018.1543398

Cited by 19 publications

(11 citation statements)

References 61 publications

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“…Other mechanisms for the development of drug resistance have been proposed 42 . Novel antiseizure agents are in development that aim to overcome drug resistance 43 . However, there is compelling evidence that multiple genetic factors influence AED response 44 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacoresponse in Genetic Generalized Epilepsy: A Genome-Wide Association Study

et al. 2020

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Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.

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Section: Discussionmentioning

confidence: 99%

Pharmacoresponse in Genetic Generalized Epilepsy: A Genome-Wide Association Study

et al. 2020

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“…Additionally, CBC reduced LPS-induced activation of murine peritoneal macrophages in vitro, an effect likely contributing to its in vivo anti-inflammatory activity [168]. Lastly, a recent report has evaluated the anti-inflammatory effects of CBDV, a compound under evaluation for the treatment of autism spectrum disorder and epilepsy/focal seizures [94,169], thus supporting its therapeutic potential. Oral CBDV reduced colonic inflammation (structural damage, inflammatory infiltrate, altered permeability and cytokine production), in the DNBS-induced colitis model in mice [128].…”

Section: Role In Inflammatory Bowel Diseasementioning

confidence: 93%

Cannabidiol and Other Non-Psychoactive Cannabinoids for Prevention and Treatment of Gastrointestinal Disorders: Useful Nutraceuticals?

Martı́nez

Iriondo‐DeHond

Borrelli

et al. 2020

IJMS

143

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Cannabis sativa is an aromatic annual flowering plant with several botanical varieties, used for different purposes, like the production of fibers, the production of oil from the seeds, and especially for recreational or medical purposes. Phytocannabinoids (terpenophenolic compounds derived from the plant), include the well-known psychoactive cannabinoid Δ9-tetrahydrocannabinol, and many non-psychoactive cannabinoids, like cannabidiol. The endocannabinoid system (ECS) comprises of endocannabinoid ligands, enzymes for synthesis and degradation of such ligands, and receptors. This system is widely distributed in the gastrointestinal tract, where phytocannabinoids exert potent effects, particularly under pathological (i.e., inflammatory) conditions. Herein, we will first look at the hemp plant as a possible source of new functional food ingredients and nutraceuticals that might be eventually useful to treat or even prevent gastrointestinal conditions. Subsequently, we will briefly describe the ECS and the general pharmacology of phytocannabinoids. Finally, we will revise the available data showing that non-psychoactive phytocannabinoids, particularly cannabidiol, may be useful to treat different disorders and diseases of the gastrointestinal tract. With the increasing interest in the development of functional foods for a healthy life, the non-psychoactive phytocannabinoids are hoped to find a place as nutraceuticals and food ingredients also for a healthy gastrointestinal tract function.

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“…CBDV is a highly liposoluble compound with a large V L (32 L/kg), it is able to rapidly penetrate the blood-brain barrier and has a poor oral bioavailability. 70 A single phase I study on healthy volunteers evaluated the PK profile of CBDV oral formulations (25,75,200, 400, 800 mg/day over 5 days) and IV preparation (5-mg, single-dose). 71 The drug was well tolerated when administered in both routes, and rapidly metabolized in the liver to 7-OH-CBDV and 7-COOH-CBDV, although the exact metabolic pathway is still unknown.…”

Section: Not Only Cbd: a Glance At Cannabidivarinmentioning

confidence: 99%

<p>Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects</p>

Morano¹,

Fanella²,

Albini³

et al. 2020

NDT

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Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ 9-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 CB 1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT 1A 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 fatcontaining 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, placebocontrolled, 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.

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Investigational small molecules in phase II clinical trials for the treatment of epilepsy

Cited by 19 publications

References 61 publications

Pharmacoresponse in Genetic Generalized Epilepsy: A Genome-Wide Association Study

Pharmacoresponse in Genetic Generalized Epilepsy: A Genome-Wide Association Study

Cannabidiol and Other Non-Psychoactive Cannabinoids for Prevention and Treatment of Gastrointestinal Disorders: Useful Nutraceuticals?

<p>Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects</p>

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