Pubdate: Wed, 18 Jan 2006
Source: Anderson Valley Advertiser (CA)
Column: Cannabinotes
Copyright: 2006 Anderson Valley Advertiser
Contact:  http://www.theava.com/
Details: http://www.mapinc.org/media/2667
Author: Fred Gardner
Bookmark: http://www.mapinc.org/pot.htm (Cannabis)
Bookmark: http://www.mapinc.org/find?323 (GW Pharmaceuticals)

COMES NOW ACOMPLIA

Even before Eli Lilly began selling Prozac in December, 1988, the 
company was selling the concept of "clinical depression" (the alleged 
disease that Prozac allegedly cures, or helps people cope with. Lilly 
also began educating doctors and the public about "selective 
serotonin reuptake inhibition," the mechanism by which Prozac allegedly works.

Sanofi-Aventis, the world's third-largest drug company, is pursuing a 
similar strategy as it awaits approval to market a drug called 
Acomplia to treat a condition called "metabolic syndrome."  In recent 
years Sanofi has been educating doctors and the public about 
"metabolic syndrome" (high glucose levels, obesity, and other risk 
factors for diabetes) and Acomplia's mechanism of action, which 
involves blocking the body's own (endo-) cannabinoid system.

Acomplia is the drug formerly known as Rimonabant. Before that it was 
known as SR141716, the SR standing for "Sanofi Recherche." It was 
developed in 1995 as an "antagonist" drug for use by researchers 
studying the endocannabinoid system. (By administering a drug that 
blocks specific receptors, scientists can infer the receptors' 
functions.)  Sanofi soon realized that its cannabinoid antagonist 
could be marketed as a weight-loss drug, and undertook a series of 
clinical trials.

Approval by the FDA and/or the European Medicines Agency is pending.

The New Scientist devoted a feature story to Acomplia Dec. 10, that 
undoubtedly convinced some readers to buy Sanofi stock. "If what has 
been made public from the clinical trials is anything to go by," 
writes Diane Martindale, "rimonabant has almost miraculous powers, 
helping people to control their appetites, shrink their waistlines 
and banish many of the metabolic problems associated with being too 
fat. And that's not all. Rimonabant has also been successfully tested 
as an aid to quitting smoking and might even be useful in treating 
alcoholism and other addictions... No wonder many industry analysts 
are backing it to become the first blockbuster drug of the 21st century...

"All four obesity trials are now complete.

Sanofi has only published one set of results, from the halfway point 
of a two-year European study involving 1507 volunteers, but if the 
results are replicated in all the trials, the drug looks like a winner...

"Investment banker JP Morgan predicts that sales will reach $5 
billion a year by 2010, which would make rimonabant one of the 
highest-grossing drugs of all time. Curiously, however, 
Sanofi-Aventis does not intend to market rimonabant for weight-loss 
or smoking cessation, preferring to cast it  as a heart medication on 
the back of the cardiovascular benefits of curbing metabolic syndrome 
and giving up cigarettes. Nor is Sanofi interested in trying to get 
the drug approved for alcohol abuse or other drug  addictions, 
despite successful tests in alcoholic rats. This could make 
good  business sense, since US health insurance companies rarely pay 
for anti-obesity drugs but will cover the cost of cardiovascular 
medication. And the regulatory agencies tend to be extra critical of 
weight-loss medications. But even  if it is marketed only as a 
medication for heart disease, the drug could be huge."

Martindale quotes weight-loss specialist Louis Aronne singing 
Acomplia's praises in a familiar cadence: 'This is the first 
effective treatment for the metabolic syndrome with weight loss as a 
side effect,'  he says. (Just as Prozac was the first effective 
treatment for clinical depression without fatal overdose as a side 
effect.) Another expert, Jason Halford, is quoted: "'This is good 
news for heart disease,' he says (sic). 'Cardiologists are looking 
for drugs to manage smoking and obesity, two things they can't do 
with existing heart disease drugs.'"

Things have changed since Prozac was introduced -the corruption of 
the system by which drugs are evaluated and approved has been widely 
exposed- and the New Scientist's Acomplia piece devotes some space to 
those expressing misgivings. "People in the obesity trials tended to 
reach  a plateau after about 34 weeks, and if they stopped taking the 
drug, they regained all the lost weight," Martindale notes. 
"Sanofi-Aventis thinks that people will be able to continue taking 
the drug indefinitely, but some obesity experts are wary."  And there 
are those who might not want to take a drug for the rest of their lives.

Also on the adverse side of the ledger: Acomplia was found to 
increase blood pressure even as it facilitated weight loss. Some 40 
per cent of Sanofi's test subjects dropped out during the first year 
of the obesity trials. "Some complained of nausea, diarrhea, 
vomiting, dizziness and headaches, as well as mood disorders 
including anxiety and depression," according to the New Scientist.

Tod Mikuriya, MD, fears that Acomplia may induce seizures and 
exacerbate or cause tumors, among other adverse effects.

Last week the Berkeley-based psychiatrist was browsing the web for 
continuing medical education classes (doctors are obligated to earn 
25 credits over four years) and came upon an expensively produced 
presentation on "The Endocannabinoid System: A Novel Therapeutic 
Target for the Management of Multiple Cardiovascular Risk Factors." 
The class consisted of talks by Sanofi-funded doctors at a 
Sanofi-funded symposium, culminating in a strong pitch for 
rimonabant. Instead of applying for his 2.5 credits, Mikuriya fired 
off an email to the FDA warning that, theoretically, blocking the CB1 
receptor system could bring on or make worse every medical condition 
for which cannabis provides relief.

He included the master list of conditions that California patients 
have reported treating efficaciously with cannabis.

Mikuriya got a reply saying that his concern had been forwarded to a 
review officer (none other than David Graham, MD, the brave FDA 
staffer who defied his bosses to tell the Senate the truth about Vioxx!

Kinder, Gentler Antagonist?

GW Pharmaceuticals has bred a plant strain rich in THCV 
(tetrahydrocannabivarin) that it hopes will provide a natural 
antagonist drug that doesn't have the liabilities of Sanofi's 
synthetic.  GW is the British pharmaceutical company that in 2005 won 
conditional approval in Canada to sell a plant extract called Sativex 
as a treatment for pain caused by multiple sclerosis.

Anecdotal evidence from seed collectors suggested that strains high 
in THCV had notably "clearer" and "faster" effects than high-THC 
strains, and GW decided to sponsor a pharmacological study by Roger 
Pertwee, MD, of the University of Aberdeen. Pertwee determined that 
THCV strongly Antagonizes anandamide -one of the body's own 
cannabinoids- while hardly antagonizing the plant cannabinoid THC! 
"The discovery that THCV was a neutral antagonist at the CB1 and then 
the CB2 receptor was a complete surprise," according to GW chairman 
Geoffrey Guy, MD. "It is therefore unlikely to be psychoactive at all 
in humans.

Even more intriguing was the fact that THCV antagonizes THC far less 
than endogenous (anandamide) or synthetic cannabinoids."

Apparently the cannabis plant contains and makes available to the 
body a choice of drugs and the body uses those it needs to achieve a 
balanced state (homeostasis).  3If the body is producing 
endocannabinoids in excess, it can use the plant cannabinoid THCV to 
achieve homeostasis,2 Guy observes. 3If the endocannabinoid system 
needs a boost, the THC  provides it (while the THCV shuts down the 
endocannabinoid system, giving it a rest as it were). The key to 
relief, apparently, is not high cannabinoid levels but proper gradients.2

GW has developed a strain with a cannabinoid content of 85% THCV and 
15% THC. (It may not be possible to have a plant that expresses 100% 
of its cannabinoid content as THCV.)  Guy says, "the possibility 
exists (yet to be demonstrated) that the extract might inhibit the 
endogenous cannabinoids whilst maintaining basic cannabinoid tone 
through the effects of THC (albeit less potently than when unopposed 
by THCV). More pharmacology is underway and we hope to take this 
extract into man this year."

GW's goal is a preparation that curbs hunger but does not drive tumor 
formation, exacerbate MS cases, lower seizure thresholds or produce 
anxiety and depression. "You want a drug that takes the edge off, not 
one that hits you like a ton of bricks," says a GW researcher who 
hopes that Sanofi's campaign to educate doctors and the public about 
metabolic syndrome will create a market for his company's kinder, 
gentler cannabioid-antagonist drug.
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MAP posted-by: Jay Bergstrom