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

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

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Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury.

“Cannabidiol (CBD) is a non-psychoactive component of marijuana, which has anti-inflammatory effects. It has also been approved by FDA for various orphan diseases for exploratory trials. Herein, we investigated the effects of CBD on liver injury induced by chronic plus binge alcohol feeding in mice. CBD may have therapeutic potential in the treatment of alcoholic liver diseases associated with inflammation, oxidative stress and steatosis, which deserves exploration in human trials.”  https://www.ncbi.nlm.nih.gov/pubmed/28935932

“Cannabidiol (CBD) is the most abundant non-psychoactive constituent of marijuana plant (Cannabis Sativa) with excellent safety profile in humans even after chronic use. In conclusion, we demonstrate that CBD treatment significantly attenuates liver injury induced by chronic plus binge alcohol in a mouse model and oxidative burst in human neutrophils. CBD ameliorates alcohol-induced liver injury by attenuating inflammatory response involving E-selectin expression and neutrophil recruitment, and consequent oxidative/nitrative stress, in addition to attenuation of the alcohol-induced hepatic metabolic dysregulation and steatosis. These beneficial effects, coupled with the proven safety of CBD in human clinical trials and its current orphan drug approval by FDA for various indications suggest that it may have therapeutic potential in liver disease associated with inflammation, oxidative stress, metabolic dysregulation and steatosis.” https://www.nature.com/articles/s41598-017-10924-8

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Medical marijuana for the treatment of vismodegib-related muscle spasm

JAAD Case Reports

“Basal cell carcinoma (BCC) arises from loss-of-function mutations in tumor suppressor patched homologue 1, which normally inhibits smoothened homologue in the sonic hedgehog signaling pathway. Vismodegib, a smoothened homologue inhibitor, is US Food and Drug Administration (FDA) approved for metastatic or locally advanced BCC that has recurred after surgery or for patients who are not candidates for surgery and radiation. Common adverse effects of vismodegib are muscle spasms, alopecia, dysgeusia, nausea, and weight loss. Muscle spasms worsen with duration of drug administration and may lead to drug discontinuation.

We report a case of vismodegib-related muscle spasm that was successfully treated with medical marijuana (MM).

During the first week of vismodegib and radiation, the patient started MM, having heard of its indication in the treatment of muscle cramps. She smoked 3 to 4 joints daily of Trainwreck strain, containing 18.6% tetrahydrocannabinol (THC), 0.0% cannabidiol (CBD), and 0.0% cannabinol. Her muscle spasms resolved immediately. She continued MM for 3.5 weeks, until the cost of MM became prohibitive. She reported no adverse effects from MM. Complete resolution of muscle spasms was sustained through the remaining 3.5 weeks of vismodegib. Complete blood count, comprehensive metabolic panel, and lactate dehydrogenase level were monitored throughout the study with no significant changes. As of 18 months posttreatment, the patient had a complete clinical response of her BCC.

One marijuana joint contains, on average, 0.66 g of marijuana, although the definition of a joint is highly variable. With any MM formulation, patients should start at a low dose and gradually titrate to effect. Additional studies could confirm safety and efficacy and better specify the optimal cannabinoid subtypes, preparations, and dosages that may be most beneficial for vismodegib-induced muscle spasms.”

http://www.jaadcasereports.org/article/S2352-5126(17)30124-8/fulltext

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Effects of Cannabinoid Agonists and Antagonists on Sleep and Breathing in Sprague-Dawley Rats.

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“There are no pharmacological treatments for obstructive sleep apnea syndrome, but dronabinol showed promise in a small pilot study. In anesthetized rats, dronabinol attenuates reflex apnea via activation of cannabinoid (CB) receptors located on vagal afferents; an effect blocked by cannabinoid type 1 (CB1) and/or type 2 (CB2) receptor antagonists. Here, using a natural model of central sleep apnea, we examine the effects of dronabinol, alone and in combination with selective antagonists in conscious rats chronically instrumented to stage sleep and measure cessation of breathing.

RESULTS:

Dronabinol decreased the percent time spent in rapid eye movement (REM) sleep. CB receptor antagonists did not reverse this effect. Dronabinol also decreased apneas during sleep, and this apnea suppression was reversed by CB1 or CB1/CB2 receptor antagonism.

CONCLUSIONS:

Dronabinol’s effects on apneas were dependent on CB1 receptor activation, while dronabinol’s effects on REM sleep were CB receptor-independent.”

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Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer.

 

“In a high percentage (≥85%) of both sporadic and familial adenomatous polyposis forms of colorectal cancer (CRC), the inactivation of the APC tumor suppressor gene initiates tumor formation and modulates the Wnt/β-Catenin transduction pathways involved in the control of cell proliferation, adhesion and metastasis.

Increasing evidence showed that the endocannabinoids control tumor growth and progression, both in vitro and in vivo.

We evaluated the effect of Rimonabant, a Cannabinoid Receptor 1 (CB1) inverse agonist, on the Wnt/β-Catenin pathway in HCT116 and SW48 cell lines carrying the genetic profile of metastatic CRC poorly responsive to chemotherapies.

Obtained data heavily supported the rationale for the use of cannabinoids in combined therapies for metastatic CRC harbouring activating mutations of β-Catenin.”

https://www.ncbi.nlm.nih.gov/pubmed/28916833

https://www.nature.com/articles/s41598-017-11688-x

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The role of cannabinoid receptors in renal diseases.

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“Chronic kidney disease (CKD) remains a major challenge for Public Health systems and corresponds to the replacement of renal functional tissue by extra-cellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for CKD except nephroprotective strategies.

The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in CKD.

Our review will first focus on the current state of knowledge regarding the cannabinoid system in normal renal physiology and in various experimental nephropathies, especially diabetes.  We will review the data obtained in models of diabetes and obesity as well as in nonmetabolic models of renal fibrosis and emphasizes the promising role of CB1 blockers and CB2 agonists in the development of renal disease and fibrosis. Next, we will review the current state of knowledge regarding the cellular pathways involved in renal fibrogenesis and renal injury.

Overall, this review will highlight the therapeutic potential of targeting the cannabinoid receptors in CKD and diabetes.”

https://www.ncbi.nlm.nih.gov/pubmed/28901271

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

“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

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Piperine-pro-nanolipospheres as a novel oral delivery system of cannabinoids: Pharmacokinetic evaluation in healthy volunteers in comparison to buccal spray administration.

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“Nowadays, therapeutic indications for cannabinoids, specifically Δ9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) are widening. However, the oral consumption of the molecules is very limited due to their highly lipophilic nature that leads to poor solubility at the aqueous environment. Additionally, THC and CBD are prone to extensive first pass mechanisms. These absorption obstacles render the molecules with low and variable oral bioavailability. To overcome these limitations we designed and developed the advanced pro-nanolipospheres (PNL) formulation. The PNL delivery system is comprised of a medium chain triglyceride, surfactants, a co-solvent and the unique addition of a natural absorption enhancer: piperine. Piperine was selected due to its distinctive inhibitory properties affecting both Phase I and Phase II metabolism. This constellation self emulsifies into nano particles that entrap the cannabinoids and the piperine in their core and thus improve their solubility while piperine and the other PNL excipients inhibit their intestinal metabolism. Another clear advantage of the formulation is its composition of materials approved for human consumption. The safe nature of the excipients enabled their direct evaluation in humans. In order to evaluate the pharmacokinetic profile of the THC-CBD-piperine-PNL formulation, a two-way crossover, single administration clinical study was conducted. The trial comprised of 9 healthy volunteers under fasted conditions. Each subject received a THC-CBD (1:1, 10mg) piperine (20mg)-PNL filled capsule and an equivalent dose of the oromucosal spray Sativex® with a washout period in between treatments. Single oral administration of the piperine-PNL formulation resulted in a 3-fold increase in Cmax and a 1.5-fold increase in AUC for THC when compared to Sativex®. For CBD, a 4-fold increase in Cmax and a 2.2-fold increase in AUC was observed. These findings demonstrate the potential this formulation has in serving as a standardized oral cannabinoid formulation. Moreover, the concept of improving oral bioavailability described here, can pave the way for other potential lipophilic active compounds requiring enhancement of their oral bioavailability.”

https://www.ncbi.nlm.nih.gov/pubmed/28890215

http://www.sciencedirect.com/science/article/pii/S016836591730843X

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Cannabidiol, a novel inverse agonist for GPR12.

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“GPR12 is a constitutively active, Gs protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay.

Our data demonstrate that cannabidiol (CBD), a major non-psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD.

CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells.

Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis.”

https://www.ncbi.nlm.nih.gov/pubmed/28888984

http://www.sciencedirect.com/science/article/pii/S0006291X1731759X

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Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

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“Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a non-euphoria producing constituent of cannabis that has the potential to relieve pain.

The aim of this study was to determine if CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy.

The therapeutic and prophylactic effects of peripheral CBD (100-300μg) were assessed. In end stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (p<0.0001; n=8). Acute, transient joint inflammation was reduced by local CBD treatment (p<0.0001; n=6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (p<0.0001; n=8), and was also found to be neuroprotective (p<0.05; n=6-8).

The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints.

These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28885454             https://insights.ovid.com/crossref?an=00006396-900000000-99152

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