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Russo E.B.,GW Pharmaceuticals
British Journal of Pharmacology | Year: 2011

Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL -1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. © 2011 The British Pharmacological Society.

The quality demands of the pharmaceutical industry require prescription medicines to be consistent in their active ingredient content. Achieving this, using raw cannabis as a feedstock, is especially challenging. The plant material is extremely inhomogeneous, and the ratios of active ingredients are affected by a range of factors. These include the genetics of the plant, the growing and storage conditions, the state of maturity at harvest, and the methods used to process and formulate the material. The reasons for this variability are described, with particular emphasis on the botanical considerations. To produce the complex botanical medicine Sativex®, which contains the cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) and a range of other ingredients, GW Pharmaceuticals had to manage these variables. This medicine, for the treatment of spasticity due to multiple sclerosis, is the first cannabis-based medicine to be approved in the UK. The company's methodology for producing this and other chemotypes is described. © 2013 John Wiley & Sons, Ltd.

News Article
Site: www.biosciencetechnology.com

Biopharmaceutical company GW Pharmaceuticals announced Monday positive results of its Phase 3 pivotal study for cannabidiol (CBD) treatment, Epidiolex, for the treatment of severe forms of epilepsy. Epidiolex is a liquid formulation of CDB, which is the most abundant non-psychoactive cannabinoid in the marijuana plant. “The results of this Epidiolex pivotal trial are important and exciting as they represent the first placebo-controlled evidence to support the safety and efficacy of pharmaceutical cannabidiol in children with Dravet syndrome, one of the most severe and difficult-to-treat types of epilepsy,” principal investigator Orrin Devinsky, M.D., of New York University Langone Medical Center’s Comprehensive Epilepsy Center, said in the announcement. “These data demonstrate that Epidiolex delivers clinically important reductions in seizure frequency together with an acceptable safety and tolerability profile, providing the epilepsy community with the prospect of an appropriately standardized and tested pharmaceutical formulation of cannabidiol being made available by prescription in the future.” Dravet syndrome is a severe treatment-resistant form of epilepsy that usually starts in infancy and is associated with a genetic mutation in sodium channels, according to the company.  There are currently no treatments for Dravet approved in the U.S. There has been anecdotal evidence that Epidiolex can control seizures, but results of the clinical trials were much anticipated. The study included 120 participants who had an average age of 10 years. Thirty percent of the patients were under the age of six. Patients were experiencing a median baseline of 13 convulsive seizures per month despite taking an average of three anti-epileptic drug (AED) treatments each.  Of the participants 61 received a 14-week treatment of Epidiolex, while 59 participants received a placebo.  The results found that patients taking the drug saw a 39 percent reduction in monthly convulsive seizures, which was statistically significant compared the 13 percent reduction in to those who received the placebo. According to the release, the drug was well tolerated, with the most common side effects including somnolence, diarrhea, decreased appetite and fatigue.  Eight patients receiving Epidiolex discontinued the study because of side effects, and as did one patient on the placebo. GW Pharmaceuticals is conducting a second Phase 3 Trial in Dravet syndrome, as well as trials for another rare and severe form of epilepsy known as Lennox-Gastaut syndrome. Epidiolex has both Fast Track Designation and Orphan Drug Designation from the U.S. Food and Drug Administration. One note of caution is that full details of the study have not been released, and will be presented at a conference in the future.

The present invention relates to the phytocannabinoid tetrahydrocannabivarin (THCV) for use in the protection of pancreatic islet cells. Preferably the pancreatic islet cells to be protected are beta cells. More preferably the protection of the pancreatic islet cells maintains insulin production at levels which are able to substantially control or improve control of blood glucose levels in a patient.

McPartland J.M.,GW Pharmaceuticals | Duncan M.,GW Pharmaceuticals | Di Marzo V.,CNR Institute of Neuroscience | Pertwee R.G.,University of Aberdeen
British Journal of Pharmacology | Year: 2015

Based upon evidence that the therapeutic properties of Cannabis preparations are not solely dependent upon the presence of Δ9-tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. Here, we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent pre-clinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action and thus appear very unlikely to produce unwanted CNS effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low-affinity CB1 ligand that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target. © 2014 The British Pharmacological Society.

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