DailyUpdates 20th April 2004: An estimated 5 million individuals suffer from rheumatoid arthritis in the Western world.  CB1 cannabinoid receptor ligands are in development as candidate treatments of this disease due to their analgesic properties.  Now researchers from the Hebrew University and the Kennedy Institute of Rheumatology in London  have demonstrated the anti-inflammatory, disease modifying efficacy of the non-psychoactive cannabinoid, HU-320 in a model of rheumatoid arthritis.

Rheumatoid arthritis is one of the more common autoimmune diseases affecting an estimated 5 million individuals around the world.  This population drives a large proportion of the $20 billion autoimmune disease market.

Since the birth of the modern pharmaceutical industry just over 100 years ago with the synthesis of aspirin, non-steroidal aspirin-like anti-inflammatory drugs (NSAIDs) have been the mainstay of the treatment of rheumatoid and other forms of arthritis. It is generally accepted that NSAIDs relieve the symptoms of arthritis such as pain and swelling without changing the course of underlying disease. There have been considerable efforts to develop drugs which modify disease progress (DMARDs) and these have met with variable success. Immunosuppressants such as cyclosporine or anti-metabolite drugs such as methotrexate are effective but have dose-limiting adverse effects. More recently various anti-tumor necrosis factor alpha (TNF-alpha) and anti-IL-1 therapies have successfully entered the market and now almost 50 molecular targets and more than 150 products being developed by nearly 100 companies (for a full analysis of DMARD R&D click here). 

Cannabinoid CB1 receptor ligands are already in development for the treatment of rheumatoid arthritis although these compounds are not DMARDs and instead act as analgesics.  Researchers at the Hebrew University of Jerusalem have however been investigating the cannabinoid system as a candidate target for future rheumatoid arthritis therapeutics and have identified a group of non-psychoactive cannabinoids that do have DMARD activity.

Cannabis sativa has long been known as a plant with anti-inflammatory properties.  Alpha9 tetrahydrocannabinol (9-THC) is a major component of marijuana and has been shown to have anti-inflammatory properties, but the psychotropic effects of this constituent preclude clinical utility.  A THC derived acid, ajulemic acid, has also been investigated over the last decade and like THC it is also a potent anti-inflammatory agent although once again it binds the central cannabinoid receptor, CB1, and parallels the CNS activity of THC.  More recently Hebrew University researchers have been collaborating with researchers at the Kennedy Institute of Rheumatology in London  and have demonstrated that cannabidiol (CBD), a non psychotropic cannabis constituent is also anti-inflammatory.  In a PNAS study published in 2000 this collaboration reported that CBD blocked progression of arthritis in 2 models of rheumatoid arthritis.  Clinical improvement was associated with protection of the joints against severe damage.  More recently these groups reported a similar effects with the novel cannabidiol derivative, HU-320

 

The anti-inflammatory activity of HU-320 is described in the March edition of Arthritis & Rheumatology.

 

In this article Sumariwalla et report the anti-arthritic potential of HU-320 in the DBA/1 mouse model of arthritis, and the in vitro anti-inflammatory and immunosuppressive effects of this molecule on macrophages and lymphocytes. The authors report that systemic daily administration of HU-320 ameliorated established CII-induced arthritis. Hind foot joints of treated mice were protected from pathologic damage. CII-specific and polyclonal responses of murine and human lymphocytes were down-modulated. HU-320 inhibited TNF production and reactive oxygen intermediates release from macrophages and suppressed the rise in serum TNF level following endotoxin challenge. HU-320 administration yielded no adverse psychotropic effects in mice.

 

These studies show that the novel synthetic cannabinoid acid HU-320 has strong antiinflammatory and immunosuppressive properties while demonstrating no psychoactive effects. The profound suppressive effects on cellular immune responses and on the production of proinflammatory mediators all indicate its usefulness as a novel nonpsychoactive, synthetic antiinflammatory product and in particular in the treatment of rheumatoid arthritis.

Source DailyUpdates 20th April; for a full abstract of the original papers see Arthritis Rheum. 2004 Mar;50(3):985-98

Recommended further reading:

• Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates

 

In this edition of DailyUpdates, LeadDiscovery also highlights epitope-specific immunotherapy as a treatment of rheumatoid arthritis...cardioprotective effects of erythropoietin in the reperfused ischemic heart...a phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer...and much more.