Ajulemic acid.

“Indevus Pharmaceuticals Inc is developing ajulemic acid, a non-steroidal anti-inflammatory drug derived from tetrahydrocannabinol, for the potential treatment of pain, inflammation and cystitis.”

http://www.ncbi.nlm.nih.gov/pubmed/16320134

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Functional and immunohistochemical characterization of CB1 and CB2 receptors in rat bladder.

“To determined the localization of CB(1) and CB(2) receptors in rat bladder and investigate the effect of a mixed CB(1)/CB(2) receptor agonist, ajulemic acid (AJA), on chemically evoked release of the sensory neuropeptide calcitonin gene-related peptide (CGRP)…

CONCLUSIONS:

CB(1) and CB(2) receptors are localized in the urothelium of rat bladder, and application of AJA inhibits the evoked release of CGRP by acting on CB(1) and CB(2) receptors.

These findings identify a potential new pathway for study in the evaluation and treatment of painful bladder syndrome/interstitial cystitis.”

http://www.ncbi.nlm.nih.gov/pubmed/18468662

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Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial.

“1′,1’dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid (CT-3), a potent analog of THC-11-oic acid, produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids. Therefore, CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain.”

 

“OBJECTIVE: To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans.”

 

“CONCLUSIONS: In this preliminary study, CT-3 was effective in reducing chronic neuropathic pain compared with placebo. No major adverse effects were observed.”

 

http://www.ncbi.nlm.nih.gov/pubmed/14519710

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High hopes for new marijuana drug

Marijuana

“Researchers have developed a synthetic compound which gives the benefits of marijuana without the high.

US researchers are developing a marijuana-derived synthetic compound to relieve pain and inflammation without the mood-altering side effects associated with other marijuana based drugs.

Professor Sumner Burstein, from the University of Massachusetts Medical School in Worcester, presented his team’s findings at last week’s national meeting of the American Chemical Society in Boston.

He is hopeful about the potential of the synthetic compound to treat a variety of conditions, including chronic pain, arthritis and Multiple Sclerosis.

The synthetic compound is called ajulemic acid, and has a formula based on that of THC. It has already produced encouraging results in animal studies of pain and inflammation, and is currently being tested on humans.

Exactly how ajulemic acid works is still under investigation but it appears to suppress chemical mediators, such as prostaglandins and cytokines, known to cause inflammation.

“We believe the compound will replace aspirin and similar drugs in most applications because of its lack of toxic side effects”, said Professor Burstein, referring to extensive animal studies, as well as a safety trial of the compound conducted in France last year among 15 healthy volunteers.

No clinically adverse effects were reported, including gastrointestinal ulcers, which have been associated with other non-steroidal anti-inflammatory compounds such as aspirin and ibuprofen.

But most significantly, no mood-altering side effects were reported. With an increasing number of medically beneficial compounds being found in marijuana, such as THC and CBD, researchers have been searching for years for ways to utilise these therapeutically without their associated “high”. They have had little success until now.

“Some people want the high,” admits Professor Burstein. “But the medical community wants efficacy without this effect.”

As well as animal studies of their own that show the compound is as potent a painkiller as morphine, Professor Burstein notes other promising animal studies that have been published. In rodent models of rheumatoid arthritis, the compound prevented joint damage. Tests of MS in rats showed the drug relieves muscle stiffness associated with the disease.

It is now undergoing tests in Germany in a group of 21 patients with chronic pain who take ajulemic acid orally twice daily, in capsule form.

Depending on these results, which will be available in about six weeks, the researchers predict the synthetic compound could be on offer by prescription within two years.

It could also be a promising alternative to current drugs used to treat arthritis, such as COX-2 inhibitors. These have been linked to adverse side effects, including heart attacks and stroke.”

http://www.abc.net.au/science/articles/2002/08/26/656786.htm?fb_action_ids=460011707368809&fb_action_types=og.likes&fb_source=aggregation&fb_aggregation_id=288381481237582

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Cannabis drug ‘fights pain without high’

   “Scientists have developed a cannabis-based medicine which relieves chronic pain without any of the “high” normally associated with the drug.

They believe the discovery could pave the way for cannabis-based medication to become available by prescription within two years.

Much of the controversy surrounding the medicinal use of cannabis has centred on fears that it would be used solely for its mood-altering effects.

However, scientists at the University of Massachusetts in the United States say their discovery should help authorities to overcome these fears.

Dr Sumner Burstein and colleagues say early trials of the medication in animals and healthy patients have been promising.

The medication, called ajulemic acid or CT3, has been manufactured in laboratories.

It maximises the medicinal effects of tertrahydrocannabinol – the key ingredient of cannabis – without any of the mind-altering effects.

‘More effective’

In animal tests, this compound was found to be between 10 to 50 times more effective at reducing pain than tetrahydrocannabinol.

Those tests showed that ajulemic acid was very effective at preventing the joint damage associated with arthritis and relieving the muscle stiffness associated with multiple sclerosis.”

Read more: http://news.bbc.co.uk/2/hi/health/2207478.stm

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Marijuana-Derived Compound Targets Pain, Inflammation

   “Researchers are developing a marijuana-derived synthetic compound to relieve pain and inflammation without the mood-altering side effects associated with other marijuana based drugs.

  They say the compound could improve treatment of a variety of conditions, including chronic pain, arthritis and multiple sclerosis. Their findings were presented at the 224th national meeting of the American Chemical Society, the world’s largest scientific society.

   The compound, called ajulemic acid, has produced encouraging results in animal studies of pain and inflammation. It is undergoing tests in a group of people with chronic pain and could be available by prescription within two to three years, the researchers say.

 “We believe that [the compound] will replace aspirin and similar drugs in most applications primarily because of a lack of toxic side effects,” says Sumner Burstein, Ph.D., lead investigator in the study and a professor in the department of biochemistry and molecular pharmacology at the University of Massachusetts Medical School in Worcester. “The indications so far are that it’s safe and effective,” he added.”

Read more: http://www.sciencedaily.com/releases/2002/08/020822071026.htm

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Suppression of human monocyte interleukin-1beta production by ajulemic acid, a nonpsychoactive cannabinoid.

Abstract

   “Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, reduces joint tissue damage in rats with adjuvant arthritis. Because interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) are central to the progression of inflammation and joint tissue injury in patients with rheumatoid arthritis, we investigated human monocyte IL-1beta and TNFalpha responses after the addition of AjA to cells in vitro… Reduction of IL-1beta by AjA may help explain the therapeutic effects of AjA in the animal model of arthritis. Development of nonpsychoactive therapeutically useful synthetic analogs of Cannabis constituents, such as AjA, may help resolve the ongoing debate about the use of marijuana as medicine.”

http://www.ncbi.nlm.nih.gov/pubmed/12566094

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Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells.

“AIMS:

To better understand mechanisms whereby Ajulemic acid (AjA), a synthetic antiinflammatory cannabinoid, promotes resolution of acute and chronic inflammation in animal models, we investigated its influence on cyclooxygenase 2 (COX2) expression and eicosanoid production in human fibroblast-like synovial cells (FLS).”

“KEY FINDINGS:

AjA increased the steady state levels of COX2 mRNA in and arachidonic acid release from FLS. Treatment of FLS with AjA increased 15-deoxy-delta(12,14)-PGJ(2) (15d-PGJ(2)) production in a concentration dependent manner, but did not affect PGE(2) production significantly.”

“SIGNIFICANCE:

The capacity of AjA to increase selectively and markedly 15d-PGJ(2), an eicosanoid which facilitates resolution of inflammation, suggests that AjA may have value as a therapeutic agent for the treatment of rheumatoid arthritis (RA) and other diseases characterized by acute and chronic inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/18840450

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Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid.

Abstract

   “Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.”

http://www.ncbi.nlm.nih.gov/pubmed/16927387

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Cannabimimetic Properties of Ajulemic Acid

   “Side effects of marijuana-based drugs and synthetic analogs of Δ9-tetrahydrocannabinol (Δ9-THC), including sedation and dysphoria, have limited their therapeutic application. Ajulemic acid (AJA), a side-chain synthetic analog of Δ8-THC-11-oic acid, has been reported to have anti-inflammatory properties without producing undesired psychoactive effects. Moreover, it has been suggested that AJA does not interact with cannabinoid receptors to produce its pharmacological effects. The aim of the present study was to conduct a thorough evaluation of the pharmacological effects of AJA then to determine whether actions at cannabinoid receptor (CB)1 mediated these effects… These studies demonstrated that AJA shares a number of CB1-mediated pharmacological properties with Δ9-THC, including cannabimimetic, discriminative stimulus, and antihyperalgesic effects. Furthermore, a separation between doses that produced antinociception and those that produced the other pharmacological effects in mice was not observed. Moreover, AJA showed nearly equipotency for therapeutic efficacy in the CFA model and for substitution in Δ9-THC discrimination. In summary, this study shows that AJA, like Δ9-THC, exhibits psychoactive and therapeutic effects at nearly equal doses in preclinical models, suggesting similar limitations in their putative therapeutic profiles.”

“Cannabis sativa (marijuana plant) has been used since antiquity for its presumed therapeutic, as well as for its euphoric effects. Although Δ9-tetrahydrocannabinol (Δ9-THC) has been identified as the major psychoactive ingredient in C. sativa, difficulty in dissociating unwanted side effects, such as sedation and psychotropic effects, from therapeutic effects has limited clinical application of Δ9-THC-based drugs. For example, dronabinol, an orally administered synthetic version of Δ9-THC, has been developed as an appetite stimulant and antiemetic for use in chronic diseases such as AIDS and cancer. In addition, recent evidence suggests oral Δ9-THC may be effective as an adjunct to opioid analgesics. The therapeutic utility of Δ9-THC, however, has been limited due to patient complaints of dysphoria and unpleasant subjective effects. Previous research has suggested that Δ9-THC carboxylic acid, one of the acid metabolites of Δ9-THC, lacks psychoactive properties of the parent compound and yet retains antinociceptive and other effects. Since this metabolite has a relatively low potency, structural changes that increased potency and stability of Δ9-THC analogs in previous structure-activity relationship studies were applied to the structure Δ9-THC carboxylic acid. The resulting compound, ajulemic acid (AJA), substitutes a 1′,1-dimethylheptyl side chain for the pentyl group of Δ9-THC and changes the Δ9-THC core structure to a more stable confirmation, Δ8-THC (Fig. 1).”

Fig. 1

 
“To date, the efficacy of AJA has been demonstrated in numerous pain and inflammation studies…”
 
“These findings also underscore the importance of thoroughly evaluating the pharmacological characteristics of novel Δ9-THC-like compounds…”
 
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