Category Archives: Multiple Sclerosis (MS)

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis.

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“A combination of molecular modeling and structure-activity relationship studies have been used to fine tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity have been synthesized and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.”

http://www.ncbi.nlm.nih.gov/pubmed/27309150

“CHROMENOPYRAZOLES: NON-PSYCHOACTIVE AND SELECTIVE CB1CANNABINOID AGONISTS WITH PERIPHERAL ANTINOCICEPTIVE PROPERTIES” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049093/

Pathways and gene networks mediating the regulatory effects of cannabidiol, a nonpsychoactive cannabinoid, in autoimmune T cells.

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“Our previous studies showed that the non-psychoactive cannabinoid, cannabidiol (CBD), ameliorates the clinical symptoms in mouse myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis model of multiple sclerosis (MS) as well as decreases the memory MOG35-55-specific T cell (TMOG) proliferation and cytokine secretion including IL-17, a key autoimmune factor.

Microarray-based gene expression profiling demonstrated that CBD exerts its immunoregulatory effects in activated memory TMOG cells via (a) suppressing proinflammatory Th17-related transcription, (b) by promoting T cell exhaustion/tolerance, (c) enhancing IFN-dependent anti-proliferative program, (d) hampering antigen presentation, and (d) inducing antioxidant milieu resolving inflammation.

These findings put forward mechanism by which CBD exerts its anti-inflammatory effects as well as explain the beneficial role of CBD in pathological memory T cells and in autoimmune diseases.”

[MEDICAL CANNABIS].

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“The cannabis plant has been known to humanity for centuries as a remedy for pain, diarrhea and inflammation.

Current research is inspecting the use of cannabis for many diseases, including multiple sclerosis, epilepsy, dystonia, and chronic pain.

In inflammatory conditions cannabinoids improve pain in rheumatoid arthritis and: pain and diarrhea in Crohn’s disease.

Despite their therapeutic potential, cannabinoids are not free of side effects including psychosis, anxiety, paranoia, dependence and abuse.

Controlled clinical studies investigating the therapeutic potential of cannabis are few and small, whereas pressure for expanding cannabis use is increasing.

Currently, as long as cannabis is classified as an illicit drug and until further controlled studies are performed, the use of medical cannabis should be limited to patients who failed conventional better established treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/27215115

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.

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“The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients.

The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.

CONCLUSIONS:

Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/27160523

A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray.

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“Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain.

A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers.

The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed.

Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day.

In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies.”

http://www.ncbi.nlm.nih.gov/pubmed/27121791

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

The multiplicity of action of cannabinoids: implications for treating neurodegeneration.

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“The cannabinoid (CB) system is widespread in the central nervous system and is crucial for controlling a range of neurophysiological processes such as pain, appetite, and cognition. The endogenous CB molecules, anandamide, and 2-arachidonoyl glycerol, interact with the G-protein coupled CB receptors, CB(1) and CB(2).

These receptors are also targets for the phytocannabinoids isolated from the cannabis plant and synthetic CB receptor ligands.

The CB system is emerging as a key regulator of neuronal cell fate and is capable of conferring neuroprotection by the direct engagement of prosurvival pathways and the control of neurogenesis.

Many neurological conditions feature a neurodegenerative component that is associated with excitotoxicity, oxidative stress, and neuroinflammation, and certain CB molecules have been demonstrated to inhibit these events to halt the progression of neurodegeneration.

Such properties are attractive in the development of new strategies to treat neurodegenerative conditions of diverse etiology, such as Alzheimer’s disease, multiple sclerosis, and cerebral ischemia.

This article will discuss the experimental and clinical evidence supporting a potential role for CB-based therapies in the treatment of certain neurological diseases that feature a neurodegenerative component.”

http://www.ncbi.nlm.nih.gov/pubmed/20875047

Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis.

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“Toll-like receptors (TLRs) are the sensors of pathogen-associated molecules that trigger tailored innate immune intracellular signalling responses to initiate innate immune reactions.

Data from the experimental autoimmune encephalomyelitis (EAE) model indicates that TLR signalling machinery is a pivotal player in the development of murine EAE. To compound this, data from human studies indicate that complex interplay exists between TLR signalling and Multiple Sclerosis (MS) pathogenesis.

Cannabis-based therapies are in clinical development for the management of a variety of medical conditions, including MS. In particular Sativex®, a combination of plant-derived cannabinoids, is an oromucosal spray with efficacy in MS patients, particularly those with neuropathic pain and spasticity.

Despite this, the precise cellular and molecular mechanisms of action of Sativex® in MS patients remains unclear. This review will highlight evidence that novel interplay exists between the TLR and cannabinoid systems, both centrally and peripherally, with relevance to the pathogenesis of MS.”

http://www.ncbi.nlm.nih.gov/pubmed/27079840

The therapeutic use of cannabinoids: Forensic aspects.

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“Since 2013 in the Italian market has been introduced the Nabiximols, a drug containing two of the main active cannabinoids: Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This drug has been approved in Italy in the treatment of Multiple Sclerosis (MS). It is an oral spray formulation and each puff of 100μl contains 2.7mg of Δ9-THC and 2.5mg of CBD.

In the present study we analyzed urine and blood samples collected from a group of 20 patients treated with Nabiximols in order to evaluate: blood Δ9-THC concentrations in relation to the dose administered and the duration of treatment and the potentiality of this medication to be used for drug habit.

The study was conducted on a sample group of patients affected by MS, of both sexes, age: 49-61 years, treated with Nabiximols for short (28 days) or long-term.

The results of our study allow affirming that it is unlikely to use this medication for drug habit or to sale it in the black market because of the low blood concentrations available and of its high costs.

These statements were confirmed by: (a) the low Δ9-THC concentrations in the pharmaceutical formulation; (b) the low blood concentrations produced by Nabiximols administration, more than 10 times smaller than the blood concentrations known to produce psychotropic effects; (c) the presence of CBD (Δ9-THC natural antagonist); (d) the route of administration (inhaled, not smoked).”

http://www.ncbi.nlm.nih.gov/pubmed/27038587

Techniques and technologies for the bioanalysis of Sativex®, metabolites and related compounds.

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“Sativex® is an oromucosal spray indicated for the treatment of moderate-to-severe spasticity in multiple sclerosis and is also an effective analgesic for advanced cancer patients.

Sativex contains Δ9-tetrahydrocannabinol (THC) and cannabidiol in an approximately 1:1 ratio.

The increasing prevalence of medicinal cannabis products highlights the importance of reliable bioanalysis and re-evaluation of the interpretation of positive test results for THC, as legal implications may arise in workplace, roadside and sports drug testing situations. This article summarizes published research on the bioanalysis of THC and cannabidiol, with particular focus on Sativex.”

http://www.ncbi.nlm.nih.gov/pubmed/27005853