Category Archives: Rheumatoid Arthritis

Immunoactive cannabinoids: Therapeutic prospects for marijuana constituents

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“Marijuana, the common name for Cannabis sativa, is a widely distributed hemp plant whose dried flowering tops and leaves have been used for medicinal purposes for 12,000 years by some estimates.

The article by Malfaitet al. in this issue of PNAS is relevant to the question of whether such traditional uses of marijuana could be clinically justifiable today.

It is conceivable that marijuana contains a series of cannabinoids that, in the aggregate, could alleviate arthritis as implied in the present report, yet remain well tolerated.

Remarkably, the claim that marijuana does so also was made 4,000 years ago by the Chinese emperor Shen-nung whose pharmacobotanical compendium, the Pen-ts’ao Ching, concluded that cannabis “undoes rheumatism””

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC34030/

Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats.

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“The hypothesis was tested that THC and anandamide elicit antinociception in the paw pressure test, and that arthritic rats would exhibit a different response.

THC and anandamide appear to release an as yet unknown endogenous opioid, because naloxone significantly blocked their effects.

This study indicates that anandamide and THC may act at different receptor sites to modulate endogenous opioid levels in mechanical nociception.”

http://www.ncbi.nlm.nih.gov/pubmed/9610941

Effects of cannabinoids on nitric oxide production by chondrocytes and proteoglycan degradation in cartilage.

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“Cannabinoids have been reported to have anti-inflammatory effects and reduce joint damage in animal models of arthritis.

This suggests a potential therapeutic role in arthritis of this group of compounds.

Cannabinoids were studied to determine whether they have direct effects on chondrocyte metabolism resulting in cartilage protection.

Synthetic cannabinoids, R-(+)-Win-55,212 (Win-2) and S-(-)-Win-55,212 (Win-3) and the endocannabinoid, anandamide, were investigated on unstimulated or IL-1-stimulated nitric oxide (NO) production in bovine articular chondrocytes as well as on cartilage proteoglycan breakdown in bovine nasal cartilage explants.

Win-2 significantly inhibited (P < 0.05) NO production in chondrocytes at 1-10 microM concentrations. The combined CB(1) and CB(2) cannabinoid receptor antagonists, AM281 and AM630, respectively, at 100 microM did not block this effect, but instead they potentiated it. Anandamide and Win-2 (5-50 microM) also inhibited the release of sulphated glycosaminoglycans in bovine cartilage explants.

The results suggest that some cannabinoids may prevent cartilage resorption, in part, by inhibiting cytokine-induced NO production by chondrocytes and also by inhibiting proteoglycan degradation.”

http://www.ncbi.nlm.nih.gov/pubmed/15670582

Arthritis and cannabinoids: HU-210 and Win-55,212-2 prevent IL-1alpha-induced matrix degradation in bovine articular chondrocytes in-vitro.

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“Cannabinoids have analgesic, immunomodulatory and anti-inflammatory properties and attenuate joint damage in animal models of arthritis.

Chondrocytes appeared to constitutively express cannabinoid receptors CB1 and CB2.

It is concluded that biologically stable synthetic cannabinoids protect cartilage matrix from degradation induced by cytokines and this effect is possibly CB-receptor mediated and involves effects on prostaglandin and nitric oxide metabolism.”

http://www.ncbi.nlm.nih.gov/pubmed/16536902

Cannabinoids: novel therapies for arthritis?

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“A key feature of osteoarthritis and rheumatoid arthritis is the loss of articular cartilage.

Cartilage breakdown is mediated by complex interactions of proinflammatory cytokines, such as IL-1, inflammatory mediators, including nitric oxide and prostaglandin E(2), and proteases, including matrix metalloproteinases and aggrecanases, such as ADAMTS-4 and -5.

Cannabinoids have been shown to reduce joint damage in animal models of arthritis.

They have also been shown to prevent IL-1-induced matrix breakdown of collagen and proteoglycan, indicating that cannabinoids may mediate chondroprotective effects.

Cannabinoids produce their effects via several cannabinoid receptors and it is important to identify the key cannabinoids and their receptors that are involved in chondroprotection.

This review aims to outline the current and future prospects of cannabinoids as anti-arthritic therapeutics, in terms of their ability to prevent cartilage breakdown.”

http://www.ncbi.nlm.nih.gov/pubmed/22530636

[MEDICAL CANNABIS – A SOURCE FOR A NEW TREATMENT FOR AUTOIMMUNE DISEASE?].

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“Medical uses of Cannabis sativa have been known for over 6,000 years. Nowadays, cannabis is mostly known for its psychotropic effects and its ability to relieve pain, even though there is evidence of cannabis use for autoimmune diseases like rheumatoid arthritis centuries ago. The pharmacological therapy in autoimmune diseases is mainly based on immunosuppression of different axes of the immune system while many of the drugs have major side effects. In this review we set out to examine the rule of Cannabis sativa as an immunomodulator and its potential as a new treatment option. In order to examine this subject we will focus on some major autoimmune diseases such as diabetes type I and rheumatoid arthritis.”

http://www.ncbi.nlm.nih.gov/pubmed/27215114

[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

Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis

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“Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive.

One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB2) is expressed primarily by immune cells.

Theoretically, selective CB2 agonists should be devoid of psychoactive effects.

In this study, we investigated therapeutic effects of a selective CB2 agonist on arthritis.

The present study suggests that a selective CB2 agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.

This is the first report of therapeutic effect of a selective CB2 agonist on CIA.

Although the effect was mild, optimization of dosage and/or treatment protocol might enhance the effect.

Perhaps, more potent selective CB2agonists might solve this problem.

Cannabinoids are pharmacologically active components of Cannabis sativa.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243420/

The synthetic cannabinoid WIN55,212-2 mesylate decreases the production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts by activating CB2, TRPV1, TRPA1 and yet unidentified receptor targets

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“Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation and cartilage destruction.

In this study we assessed the ability of WIN to modulate cytokine and MMP-3 production in SFs over a wide concentration range and identified specific receptor targets that mediate the effects of this synthetic cannabinoid.

The synthetic cannabinoid WIN in low concentrations exhibits anti-inflammatory effects in synovial fibroblasts independent of CB1 and CB2 while CB2 and yet unidentified receptor targets are responsible for WIN effects in micromolar concentrations.

Our results indicate a TRPV1/TRPA1 dependent mechanism of SF regulation that might be coupled to cellular energy status and calcium content.

In this report we demonstrated anti-inflammatory effects of the synthetic cannabinoid WIN in low and high concentrations.

Furthermore, this study demonstrated anti-inflammatory effects via modulation of TRP channels by WIN. Together, inactivation of TRPs and activation of cannabinoid receptors might also reduce the sensation of pain, which further underlines the potential of WIN in the treatment of chronic inflammation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858820/

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