Monthly Archives: May 2017

Pharmacogenetics of Cannabinoids.

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 European Journal of Drug Metabolism and Pharmacokinetics

“Although the application of medical marijuana and cannabinoid drugs is controversial, it is a part of modern-day medicine.

The list of diseases in which cannabinoids are promoted as a treatment is constantly expanding. Cases of significant improvement in patients with a very poor prognosis of glioma or epilepsy have already been described. However, the occurrence of side effects is still difficult to estimate, and the current knowledge of the therapeutic effects of cannabinoids is still insufficient.

In our opinion, the answers to many questions and concerns regarding the medical use of cannabis can be provided by pharmacogenetics. Knowledge based on proteins and molecules involved in the transport, action, and metabolism of cannabinoids in the human organism leads us to predict candidate genes which variations are responsible for the presence of the therapeutic and side effects of medical marijuana and cannabinoid-based drugs.

We can divide them into: receptor genes-CNR1, CNR2, TRPV1, and GPR55, transporters-ABCB1, ABCG2, SLC6A, biotransformation, biosynthesis, and bioactivation proteins encoded by CYP3A4, CYP2C19, CYP2C9, CYP2A6, CYP1A1, COMT, FAAH, COX2, ABHD6, ABHD12 genes, and also MAPK14. This review organizes the current knowledge in the context of cannabinoids pharmacogenetics according to individualized medicine and cannabinoid drugs therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/28534260

“There is a feeling that the next milestone, after legal acceptance of medical marijuana, will be intensive pharmacogenetic-oriented study of individual populations, which hopefully explain the previous contradictory results and identify in the future genetic markers to personalize cannabinoids treatment.” https://link.springer.com/article/10.1007%2Fs13318-017-0416-z

 

Targeting cannabinoid signaling for peritoneal dialysis-induced oxidative stress and fibrosis.

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“Long-term exposure to bioincompatible peritoneal dialysis (PD) solutions frequently results in peritoneal fibrosis and ultrafiltration failure, which limits the life-long use of and leads to the cessation of PD therapy. Therefore, it is important to elucidate the pathogenesis of peritoneal fibrosis in order to design therapeutic strategies to prevent its occurrence. Peritoneal fibrosis is associated with a chronic inflammatory status as well as an elevated oxidative stress (OS) status. Beyond uremia per se, OS also results from chronic exposure to high glucose load, glucose degradation products, advanced glycation end products, and hypertonic stress. Therapy targeting the cannabinoid (CB) signaling pathway has been reported in several chronic inflammatory diseases with elevated OS. We recently reported that the intra-peritoneal administration of CB receptor ligands, including CB1 receptor antagonists and CB2receptor agonists, ameliorated dialysis-related peritoneal fibrosis. As targeting the CB signaling pathway has been reported to be beneficial in attenuating the processes of several chronic inflammatory diseases, we reviewed the interaction among the cannabinoid system, inflammation, and OS, through which clinicians ultimately aim to prolong the peritoneal survival of PD patients.”

https://www.ncbi.nlm.nih.gov/pubmed/28540200

http://www.wjgnet.com/2220-6124/full/v6/i3/111.htm

Correlation Between Cannabidiol-Induced Reduction of Infarct Volume and Inflammatory Factors Expression in Ischemic Stroke Model.

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“Recent studies demonstrated that cannabidiol had neuroprotective property. There is some evidence about effective role of cannabidiol in reduction of ischemic damages. It has been reported that infarct size is influenced by various factors after MCAO, including inflammatory factors. The aim of the present study was to evaluate the effect of cannabidiol on infarction volume and correlation of infarct size with tumor necrosis factor receptor 1 (TNFR1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression.

RESULTS:

The present results indicate that in the MCAO-induced cerebral ischemia, administration of cannabidiol (100 and 200 ng/rat) causes a significant reduction in infarction volume in comparison with the vehicle group. Also, there were significant correlations between decrease of regional infarct volume and TNFR1/NF-κB expression.

CONCLUSION:

The results of this study indicate that cannabidiol reduced cerebral infarction possibly through diminishing TNFR1/NF-κB-induced neurotoxicity in transient focal cerebral ischemia.”

 https://www.ncbi.nlm.nih.gov/pubmed/28539998
http://bcn.iums.ac.ir/article-1-708-en.html

Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome

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“BACKGROUND

The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.

METHODS

In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.

RESULTS

The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.

CONCLUSIONS

Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)”

http://www.nejm.org/doi/10.1056/NEJMoa1611618

“Cannabinoids for Epilepsy — Real Data, at Last”  http://www.nejm.org/doi/full/10.1056/NEJMe1702205

“Cannabidiol (CBD) Significantly Reduces Convulsive Seizure Frequency in Dravet Syndrome (DS): Results of a Multi-center, Randomized, Double-blind, Placebo-controlled Trial (GWPCARE1)” http://files.shareholder.com/downloads/AMDA-1TW341/201889199x0x919787/73B57FA6-CD45-4ABB-8C89-87EFEA36B4ED/1332B_AES_Poster_Dravet_Part_B_.pdf

“EPILEPSY AND MARIJUANA: CANNABIS DRUG REDUCES DRAVET SYNDROME SEIZURES IN LARGE-SCALE CLINICAL TRIAL” http://www.newsweek.com/cannabis-marijuana-dravet-syndrome-epilepsy-clinical-trial-614982

“Study proves medicinal cannabis can help children with severe epilepsy, researchers say” http://www.abc.net.au/news/2017-05-25/scientific-study-medicinal-cannabis-helps-children-with-epilepsy/8556180
 
 
 

Systematic review of the potential role of cannabinoids as antiproliferative agents for urological cancers.

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“The palliative effects of cannabis sativa (marijuana), which include appetite stimulation, attenuation of nausea and emesis, and pain relief, are well known.

The active components of cannabis sativa (cannabinoids) and their derivatives have received growing interest due to their diverse pharmacological activities, such as cell growth inhibition and tumour regression.

The aim of this review is to look at the current evidence on the antiproliferative effects of cannabinoids in urological malignancies, including renal, prostate, bladder, and testicular cancers.

The search yielded a total of 93 studies from Medline and PubMed, of which 23 studies were included in the final analysis. To date, there are various in vitro studies elucidating the potential mechanism of action of cannabinoids for urological cancers, along with population-based studies specifically for testicular malignancies. To date, no clinical trials have been conducted for urological cancer patients.

These results demonstrate that the role of endocannabinoids for urological malignancies is an area of active research. Further research is required not only to evaluate the crosstalk between cancer signaling pathways and cannabinoids, but also large randomized clinical studies with urological patients need to be conducted before cannabinoids can be introduced as potential therapeutic options for urological neoplasms.”

https://www.ncbi.nlm.nih.gov/pubmed/28515817

http://www.cuaj.ca/index.php/journal/article/view/4371

Cannabis as medicine

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“Evidence supports reform to allow the legitimate study, regulation, and prescription of therapeutic cannabinoids.hemp

From its first recorded uses in China through to the early 20th century, cannabis has had a place in the pharmacopoeia. Queen Victoria’s personal physician, Russel Reynolds, opined in the Lancet in 1890, “Indian hemp, when pure and administered carefully, is one of the most valuable medicines we possess.” This opinion was based on current best evidence: the careful and documented observation of its effects in medical conditions.

In a similar vein, calls have been made to reconsider the role of cannabis in today’s society. Two well informed British politicians recently told The BMJ, “We have heard striking testimonies from patients… that cannabis has ‘given them their life back.’” Added to this, the international position on cannabis as a potential medication has changed, with international agencies and many governments relaxing a prohibitionist stance.”

http://www.bmj.com/content/357/bmj.j2130

Cannabidiol in Medical Marijuana: Research Vistas and Potential Opportunities.

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“The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects.

The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC.

Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties.

It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD.

Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.” https://www.ncbi.nlm.nih.gov/pubmed/28501518

http://www.sciencedirect.com/science/article/pii/S1043661817303559

Neuroprotection in oxidative stress-related neurodegenerative diseases: role of endocannabinoid system modulation.

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“Redox imbalance may lead to overproduction of reactive oxygen and nitrogen species (ROS/RNS) and subsequent oxidative tissue damage which is a critical event in the course of neurodegenerative diseases. It is still not fully elucidated, however, whether oxidative stress is the primary trigger or a consequence in process of neurodegeneration.

Recent Advances: Increasing evidence suggests that oxidative stress is involved in the propagation of neuronal injury and consequent inflammatory response, which in concert promote development of pathological alterations characteristic of most common neurodegenerative diseases.

Critical Issue: Accumulating recent evidence also suggests that there is an important interplay between the lipid endocannabinoid system (ECS; comprising of the main cannabinoid 1 and 2 receptors (CB1 and CB2), endocannabinoids and their synthetic and metabolizing enzymes) and various key inflammatory and redox-dependent processes.

FUTURE DIRECTIONS:

Targeting the ECS in order to modulate redox state-dependent cell death, and to decrease consequent or preceding inflammatory response holds therapeutic potential in multitude of oxidative stress-related acute or chronic neurodegenerative disorders from stroke and traumatic brain injury to Alzheimer`s and Parkinson`s diseases, and multiple sclerosis, just to name a few, which will be discussed in this overview.”

 https://www.ncbi.nlm.nih.gov/pubmed/28497982

Continuous Intrathecal Infusion of Cannabinoid Receptor Agonists Attenuates Nerve Ligation-Induced Pain in Rats.

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“Cannabinoid receptors (CB1R/CB2R) are known to play important roles in pain transmission.

In this study, we investigated the effects of continuous intrathecal infusion of CB1/2R agonists in the L5/6 spinal nerve ligation pain model.

Continuous intrathecal infusion of CB1/2R agonists elicits antinociception in the pain model.

The mechanisms might involve their actions on neurons and glial cells. CB2R, but not CB1R, seems to play an important role in the regulation of nerve injury-induced neuroinflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/28492437

Antimicrobial Activity of Cannabis sativa L.

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“The oil of the seeds, petroleum ether and methanol extracts of the whole plant of Cannabis sativa belonging to the family Cannabinaceae were screened for their antimicrobial activity against two Gram positive organisms (Bacillus subtilis, Staphylococcus aureus), two Gram negative organisms (Escherichia coli, Pseudomonas aeruginosa) and two fungi namely Aspergillus niger and Candida albicans using the cup plate agar diffusion method.

The oil of the seeds of Cannabis sativa exerted pronounced antibacterial activity (21 – 28 mm) against Bacillus subtilis and Staphylococcus aureus, moderate activity (15 mm) against Escherichia coli and high activity (16 mm) against Pseudomonas aeruginosa and inactive against the two fungi tested. The petroleum ether extract of the whole plant exhibited pronounced antibacterial activity (23 – 28 mm) against both Bacillus subtilis and Staphylococcus aureus organisms, high activity (16 mm) against Escherichia coli and inactive against Pseudomonas aeruginosa and both fungi. The methanol extract of the whole plant showed also pronounced antibacterial activity (29 mm) against Bacillus subtilis, low activity (12 mm) against Staphylococcus aureus and high activity (16 – 18 mm) against both Gram negative organisms, inactive against Aspergillus niger and low activity (13 mm) against Candida albicans.

The minimum inhibitory concentrations of Cannabis sativa methanol extracts of the seeds and the whole plant against the standard organisms were determined using the agar plate dilution method. The standard organisms were tested against reference antibacterial and antifungal drugs and the results were compared with the activity of the extracts.”

http://www.scirp.org/journal/PaperInformation.aspx?PaperID=18123