ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“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

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Therapeutic potential of cannabinoid medicines.

Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

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Medicinal marijuana stops seizures, brings hope to a little girl – NBC

“Six-year-old Charlotte Figi, a picture of precious in her “Gatsby”-style bob and blue toenails, stands patiently as her mother reaches up her dress to change her out of her soiled Pull-Ups.”

Read more on Colorado Springs Gazette

http://www.nbcnews.com/id/52147512/ns/local_news-colorado_springs_co/t/medicinal-marijuana-stops-seizures-brings-hope-little-girl/

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‘Milestone’ epilepsy drug based on cannabis

A collaboration between a UK research team and international medicine manufacturers may lead to a ‘milestone’ treatment for epilepsy. This treatment appears more bearable than current epilepsy medicines – and is based on cannabis.

A research team at the University of Reading performed the research, which was recently published in The British Journal of Pharmacology. Their research explored the use of cannibidivarin – a natural chemical called a ‘cannabinoid’ from the cannabis plant.

Cannibidivarin does not have psychoactive properties (anyone taking a drug based on this chemical will not feel ‘high’ as a result). It appears to reduce seizure frequency in laboratory animals with epilepsy and has fewer side-effects than traditional epilepsy medicines. The new drug can also be safely combined with regular medications.

Lead study author, Dr Ben Whalley, said: “This is an enormously exciting milestone in our investigations into non-psychoactive elements of cannabis as treatments for epilepsy. Our work has highlighted the potential for a solution based on cannabinoid science. It has shown that cannabidivarin is the most effective and best tolerated anticonvulsant plant cannabinoid investigated to date.””

More: http://www.epilepsy.org.uk/news/news/%E2%80%98milestone%E2%80%99-epilepsy-drug-based-cannabis

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Marijuana and its receptor protein in brain control epilepsy

“VCU study is first to test anticonvulsant potential of marijuana and brain recurrent seizures. 

Ingredients in marijuana and the cannabinoid receptor protein produced naturally in the body to regulate the central nervous system and other bodily functions play a critical role in controlling spontaneous seizures in epilepsy, according to a new study by researchers at Virginia Commonwealth University.

The study, the first to look at marijuana and the brain’s cannabinoid system in live animals with spontaneous, recurrent seizures, suggests new avenues that researchers can explore in their search for more-effective drugs to treat epileptic patients who don’t respond to today’s anticonvulsant medications or surgery.

The results appear in the Oct. 1 issue of the Journal of Pharmacology and Experimental Therapeutics.

“Although marijuana is illegal in the United States, individuals both here and abroad report that marijuana has been therapeutic for them in the treatment of a variety of ailments, including epilepsy,” says Dr. Robert J. DeLorenzo, professor of neurology in the VCU School of Medicine.

 “If we can understand how marijuana works to end seizures, we may be able to develop novel drugs that might do a better job of treating epileptic seizures.” 

Epilepsy is one of the most common neurological conditions, characterized by spontaneously recurrent seizures. Approximately 1 percent of Americans have epilepsy, and 30 percent of those patients are resistant to conventional anticonvulsant drug treatments.

Cannabinoids have been used as a natural remedy for seizures for thousands of years, and studies since at least 1974 have found that the primary psychoactive compound in marijuana displays anticonvulsant properties.” 

More:http://www.news.vcu.edu/news/Marijuana_and_its_receptor_protein_in_brain_control_epilepsy

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Children with epilepsy need medical marijuana

“Medical marijuana shouldn’t be for ‘adults only’.

My 9-year-old daughter has Aicardi syndrome, a rare genetic disorder that causes extremely hard-to-control seizures, debilitation, disability and early mortality. She began having seizures at three months of age, and since that time has had multiple seizures every day, with rare exception — probably to the tune of nearly 200,000 seizures in her lifetime…

She is one of the 3 million Americans who have epilepsy, and one of the 40 percent whose seizures cannot be controlled by anti-seizure drugs. She has tried 10 anti-seizure medications as well as a high-protein/low-carbohydrate diet called the ketogenic diet; she takes three anti-seizure medications at once and has a vagus nerve stimulator implant that sends mild electrical pulses to the brain. These drugs help her, but she nonetheless experiences an average of three seizures every day. Moreover, the medications cause persistent side effects that negatively impact her quality of life, particularly her gastrointestinal, bone, dental, cognitive and mental health.

The Illinois Senate Executive Committee recently voted, 10-5, to move the House-passed medical marijuana legislation to the Senate for a vote. The bill is expected to pass, and though Gov. Pat Quinn has not committed to signing it, the general expectation is that the bill will become law. This should be received as great news for the many people with “debilitating” conditions that the bill is supposed to help — people for whom medical science has documented real, measurable and safe outcomes of the controlled use of cannabis or its component of chemical compounds.

It’s too bad that the legislature has ignored the medical needs of some of the most debilitated, and most vulnerable, patients in the state: children with epilepsy.

Imagine her father’s and my reaction upon learning that the legislature, in its concern not to send a “message” to kids that it is safe to smoke marijuana, decided that kids like ours, for whom medical cannabis has the potential to be as safe and effective as typical anti-seizure drugs, should be excluded from the benefits of this new law.

They have done so, I hope, only out of ignorance…

There is no likelihood that my daughter will become a drug addict from using a compound within cannabis in a medically controlled setting. There is, however, a good chance that participation in a controlled study of these compounds could open the door to new treatments for her, and the many children like her, who desperately need medical innovation to save or improve their lives.”

More: http://articles.chicagotribune.com/2013-05-15/opinion/ct-oped-0515-marijuana-20130515_1_dravet-seizures-medical-cannabis

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The endocannabinoid system and its therapeutic exploitation.

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“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”  http://www.ncbi.nlm.nih.gov/pubmed/15340387

http://www.nature.com/nrd/journal/v3/n9/full/nrd1495.html

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From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

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“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”

http://www.ncbi.nlm.nih.gov/pubmed/23155985

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Compound in cannabis may help treat epilepsy, researchers say

“British researchers have determined that a little-studied chemical in the cannabis plant could lead to effective treatments for epilepsy, with few to no side effects.

The team at Britain’s University of Reading, working with GW Pharmaceuticals and Otsuka Pharmaceuticals, tested cannabidivarin, or CBDV, in rats and mice afflicted with six types of epilepsy and found it “strongly suppressed seizures” without causing the uncontrollable shaking and other side effects of existing anti-epilepsy drugs.

The casual use of marijuana — or cannabis — to control seizures dates back to ancient times. Its most prominent component, THC, is among those shown in animal studies to have strong anti-convulsant properties…”

http://articles.latimes.com/2012/sep/14/news/la-sn-cannabis-cbdv-epilepsy-20120914

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Cannabidivarin is anticonvulsant in mouse and rat.

“Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models.”

 

“CONCLUSIONS AND IMPLICATIONS:

These results indicate that CDBV is an effective anticonvulsant across a broad range of seizure models, does not significantly affect normal motor function and therefore merits further investigation in chronic epilepsy models to justify human trials.”

http://www.ncbi.nlm.nih.gov/pubmed/22970845

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