Icariin from horny goat weed is structurally unrelated to sildenafil (Viagra®)

In our last post, we discussed a recent USPTO ruling that rejected a claim of the Pfizer patent on the erectile dysfunction drug, sildenafil (Viagra®), to a novel oral treatment for the disorder. The patent appeals panel ruled that the existence of horny goat weed, a traditional Chinese medicine used orally for impotence, was grounds for rejection of the claim.
Frequent commenter daedalus4u pulled out US Patent #6,469,012 (filed Mar 4 1996, issued Oct 22 2002) wherein the relevant claim 24 reads:

A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a selective cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, of a pharmaceutical composition containing either entity.

The claim should never have been allowed in the first place, said daedalus4u, and if upheld would have allowed Pfizer to block sales of horny goat weed. I’m also assuming that upholding claim 24 would have also allowed Pfizer to block sales of follow-on PDE5 inhibitors such as Lilly’s Cialis®. But again, I’m not a patent attorney so I welcome further discussion on this point.
We also heard from my dear old colleague from Adelaide, Professor Ian Musgave. Ian is a pharmacologist who is probably better known in the blogosphere for his astronomy expertise (Astroblog, Southern Sky Watch, and contributing editor to Sky & Space).
But Ian is first and foremost a pharmacologist and raised this point:

Wait a minute, let me get this straight. The patent on Sildenafil, a compound that was rationally designed to specifically inhibit PDE (1) and developed prior to 1996 was invalidated because of a structurally unrelated component of a herbal extract that wasn’t even shown to act on the cGMP/NO system before 2001? (2)

Pfizer is supposed to have time travel? The fact that a herbal treatment alleged to help sexual function would turn out, 5 years after the sildenafil patent had been granted (and the concept of PDE5 inhibitors as treatment for erectile dysfunction wide spread) to have effects on PDE5 could not possibly count as prior art. If so, the 1983 demonstration that the PDE inhibitor papaverine could produce erections would have invalidated the sildenafil patent.

The patent boards ruling is patently rubbish. How can sildenafil “logically flow” from a compound that wasn’t even known to really work, let alone known to inhibit PDE?

(1)Nicholas K. Terrett, Andrew S. Bell, David Brown and Peter Ellis. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorganic & Medicinal Chemistry Letters
Volume 6, Issue 15, 6 August 1996, Pages 1819-1824
(2)Xin ZC. Kim EK, Tian ZJ, Lin GT, Guo YL. Icariin on relaxation of corpus cavernosm smooth muscle. Chin Sci Bulle 2001; 46: 485-9.

Prof Musgrave is indeed correct in the argument but daedalus4u points out the ruling did not invalidate the Pfizer patent, just the single claim to the pharmaceutical indication.
So that makes more sense to me and now I think I understand.
But in the discussion, Ian gave us another gem in response to a commenter who argued there was a structural resemblance between sildenafil and icariin, the active flavonol glycoside constituent of horny goat weed:

No, not at all. You can stick the benzofuran of the flavonol on top of the methylxanthine moiety of the sildenafil, but the charge distribution and 3D structure is all wrong, the flavonol has these huge sugar moieties which have the wrong charge and stick out in places that should inhibit binding, it lacks the bulky positively charged ring that fits into the PDE5 specific binding pocket. (I have the an image of the 3D structural overlay if anyone want to see them).
Looking at it, icariin does not scream either methylxanthine mimetic or “PDE inhibitor”, in fact I would guess it would be worthless. However, flavonols and flavinoids have a habit of doing things we don’t expect, such as resveratrol being a very decent cannaboid receptor anatgonist, despite looking nothing like cannabinoids of the synthetic antagonists.

In fact, Ian was kind enough to send us two molecular modeling images of the two compounds which I failed to get posted last night that illustrate the vast difference between sildenafil and icariin. This overlay image was generated with RASMOL, with icariin in the wireframe format and sildenafil in stick format:

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Horny Goat Weed (Epimedium spp.) is a limp excuse for Viagra, Cialis

Reuters and Bloomberg reported earlier this week on an ongoing patent battle (read: pissing match) between Pfizer and Eli Lilly & Co. relating to their erectile dysfunction drugs Viagra and Cialis, respectively.
Goat.jpgA US Patent and Trademark Office (USPTO) appeals committee has ruled that an element of Pfizer’s patent on sildenafil, the active chemical in Viagra, is invalid because the drug is insufficiently different from a traditional Chinese medicine called Yin Yang Huo or horny goat weed.
At issue is Pfizer’s claim to a method for treating male erectile dysfunction. The patent appeals panel ruled that the method did not constitute a new invention because of the precedent set by Yin Yang Huo. Moreover, the board ruled that chemicals found in the herbal medicine act by the same mechanism as sildenafil by inhibition of an enzyme called phosphodiesterase-5 (PDE5). Therefore, the panel ruled, “the patent claim was the next logical step up from using the herb.”
I’m not an expert in law but there are untold number of traditional remedies touted for all sorts of sexual enhancement, none of which have the convincing efficacy of the prescription PDE5 inhibitors. We may call the condition “erectile dysfunction” today and the idea of treating it may have existed for centuries but having a compound that can actually do anything about it is an invention. However, I can see the fine distinction if Pfizer claimed that the idea of treating erectile dysfunction was an invention.
You lawyers out there can weigh in but this sounds like a bunch of posturing for market share: worldwide Viagra sales were $2 billion USD last year.
But what is this horny goat weed and why is it being singled out?

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MuscleMaster.com “voluntarily” recalls 17 steroid-laden dietary supplements

It seems that bodybuilding supplement makers are challenging erectile dysfunction supplement makers to see who can recall the greatest number of products adulterated with undeclared, unapproved drugs.
In this case, an internet retailer of the following supplements has issued a voluntary recall of the following supplements sold between June 1, 2009 and November 17, 2009. The recall follows an FDA warning letter on detection of undeclared, synthetic anabolic steroids in these products:

  • Advanced Muscle Science Dienedrone, 60 caps
  • Advanced Muscle Science Liquidrone, 60 ml
  • Anabolic Formulation M1, 4AD, 60 caps
  • Anabolic Formulations 1, 4 AD, 60 caps
  • Anabolic Xtreme Hyperdrol X2
  • Anabolic Xtreme 3-AD, 90 caps
  • BCS Labs Testra-Flex, 90 caps
  • Competitive Edge Labs M-Drol, 90 Caps
  • Competitive Edge Labs P-Plex, 90 caps
  • Competitive Edge Labs X-Tren, 90 caps
  • 4Ever Fit D-Drol, 60 caps
  • Gaspari Novedex XT 60 Caps
  • Gaspari Halodrol Liquigels, 60 gels
  • iForce 1,4 AD BOLD 200, 60 Caps
  • iForce MethaDROL, 90 caps
  • iForce Dymethazine, 60 caps
  • Monster Caps, 60 caps

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Unusual unapproved drug action by FDA against Provident Pharmaceuticals

In an article by Wayne Heilman of the Colorado Springs Gazette, I learned of a US FDA action against contract drug manufacturer Provident Pharmaceuticals. The company has been cited for good manufacturing practices (GMP) violations as well as the manufacture of unapproved drugs. The GMP violations are of a magnitude that FDA requested that Provident hire a GMP training consultant to bring the facility up to snuff.
However, Heilman seized upon an interesting side light in the warning: the names of the unapproved drugs apparently made by the company are missing from the detailed warning letter.
By unapproved drugs, FDA means drugs whose safety and efficacy has not been formally investigated under modern criteria. Some of these agents are those which the average person might say, “Really? That was never approved? You’re kidding, right?”
I suspect this is an innocent omission – I hypothesize that Provident wasn’t doing anything nefarious – because FDA has been widely aggressive in acting against companies marketing such old drugs, a topic that deserves its own post. In the meantime, the reader may care to visit this Unapproved Drugs site at fda.gov.
A good example is the expectorant, guaifenesin, a natural product isolated for trees of the Guaiacum genus. This compound, a racemic mixture actually, was approved by FDA in 1952 to increase the volume and reduce the viscosity of respiratory secretions. However, it was never formally approved after the 1962 legislation that gave the US most of its current guidelines for preclinical and clinical drug testing.
When FDA began its current enforcement campaign against unapproved drug manufacturers, Reckitt Benckiser seized upon guaifenesin being an unapproved drug, brought it up to modern standards, and now has a top-selling product with Mucinex, accompanied by those animated mucus blob characters that either charm or repulse.

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Conservative author David Frum: “Repeal DSHEA”

David Frum.jpgBy most metrics, those of us at Terra Sig World Headquarters are liberals. Nevertheless, we often enjoy reading conservative writer, attorney, and American Enterprise Institute fellow, David Frum. Perhaps I have a soft spot for him because he’s Canadian and he also writes for my favorite print newsmagazine, The Week.
Well, Frum chose this week to write, “Herbal remedies need real scrutiny,” at his FrumForum and the post was subsequently published as a special commentary at CNN.com. The latter version has accumulated about ten times as many comments. The thesis of his essay is that the differential regulation of drugs and dietary supplements is flawed and ends with this paragraph:

Improving and rationalizing this costly and dysfunctional system is a gigantic, maybe impossible, task. But one small reform could strike a meaningful blow for reason and cost-effectiveness: Apply the rules governing the advertising of aspirin to the advertising of oregano tablets. Repeal the DSHEA law and give the Food and Drug Administration full authority over every manufactured substance that purports to promote health or relieve illness.

DSHEA is the Dietary Supplement and Health Education Act of 1994 that governs, among other things, the claims that may be made for herbal and non-botanical products not subjected to conventional and rigorous preclinical and clinical studies.
But it gets better.

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The University of Texas M.D. Anderson Cancer Center takes legal action against Evolv water

Thumbnail image for Thumbnail image for dontmesswithtexas.jpgIn September we posted “M.D. Anderson name misused in Evolv nutraceutical water advertising,” detailing the not-exactly-truthful claim by a multilevel marketing company that their bottled water product was “tested” by one of North America’s premier teaching and research hospitals.
A flurry of search engine hits to this post raised my attention to the fact that the The University of Texas M.D. Anderson Cancer Center has now initiated legal action against the makers of Evolv. Cameron Langford at Courthouse News Service reports:

Two companies are pushing bottled tap water with false claims that it’s endorsed by the MD Anderson Cancer Center, the University of Texas says in Federal Court. The UT says HealtH20 Products and Evolvehealth sell the bogus water it as “Evolv,” claiming it is infused with an “Archaea Active formula.” [. . .]
[. . .] “Specifically, defendants are misleading consumers and cancer patients into believing that UT’s MD Anderson conducted extensive testing of the main formula in the Evolv product, known as ‘Archaea Active,” the UT says.
“Defendants’ misuse of the MD Anderson marks creates, at a minimum, a likelihood that cancer patients and consumers will falsely believe that defendants’ products is sponsored or endorsed by UT’s MD Anderson, when in fact, MD Anderson does not endorse or recommend the use of the defendants’ product.”

Natural products researchers, including yours truly, are used to supplement companies misrepresenting our published papers in their advertising literature. There’s not much we can do as individuals when our work is cited on a webpage.
However, there’s a much more serious issue going on in this case: according to the official complaint filed against the companies by the Board of Regents of The University of Texas System (PDF here from Courthouse News) M.D. Anderson and The University of Texas M.D. Anderson Cancer Center are registered US trademarks.

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“Stiff Nights” Falls on Hard Times

Stiff Nights.jpgI should probably create a new blogpost category just for erectile dysfunction dietary supplements adulterated with authentic or synthetic analogs of prescription phosphodiesterase-5 (PDE5) inhibitors (e.g., Viagra, Cialis).
However, FDA has already created a page for this earlier this year after dozens of companies have been identified as putting real drugs into their erectile dysfunction products.
Do the brains behind these companies not realize that FDA is now monitoring every erectile dysfunction supplement for all manner of PDE5 inhibitors?
Apparently not:

For Immediate Release: Nov. 5, 2009
Media Inquiries: Christopher Kelly, 301-796-4676, christopher.kelly@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA Warns Consumers on Sexual Enhancement Products
Another dietary supplement is found to be contaminated with potentially dangerous ingredient
FDA Hidden risks of ED products online.jpgThe U.S. Food and Drug Administration is warning consumers that Stiff Nights, a product marketed as a dietary supplement for sexual enhancement, contains an ingredient that can dangerously lower blood pressure and is illegal.
Over the past several years, the FDA has found many products marketed as “dietary supplements” for sexual enhancement that contain undeclared active ingredients of FDA-approved drugs, analogs of approved drugs and other compounds that do not qualify as “dietary ingredients.” The FDA has issued multiple alerts about these contaminated dietary supplements.
Consumers and health care professionals should be aware of this problem and the health hazard it presents. Sexual enhancement products that claim to work as well as prescription products are likely to contain a contaminant. Use of such products exposes consumers to unpredictable risk and the potential for injury or even death.
In the case of Stiff Nights, following a consumer complaint, the FDA determined that the product contains sulfoaildenafil. This is a chemical similar to sildenafil, the active ingredient in Viagra. Sulfoaildenafil may interact with prescription drugs known as nitrates, including nitroglycerin, and cause dangerously low blood pressure.
The product is distributed on Internet sites and at retail stores by Impulsaria LLC of Grand Rapids, Mich. It is sold in bottles containing 6, 12, or 30 red capsules or in blister packs containing one or two capsules.
“Because this product is labeled as an ‘all natural dietary supplement,’ consumers may assume it is harmless and poses no health risk,” said Deborah M. Autor, director of FDA’s Center for Drug Evaluation and Research Office of Compliance. “In fact, this product is illegally marketed and can cause serious complications.”
The FDA advises consumers who have experienced any adverse events from sexual enhancement products to consult a health care professional. Consumers and health care professionals should report adverse events to the FDA’s MedWatch program at 800-FDA-1088 or online at http://www.fda.gov/medwatch/report.htm
The FDA remains committed to stopping the illegal marketing of unapproved drugs and will continue to protect the public with vigorous law enforcement and criminal prosecution of violators.

I’ll be very serious about this for a moment because, in this particular case, it appears that FDA was acting on a consumer complaint that I suspect arose from an adverse health reaction to the product. Taking a PDE5 inhibitor on top of prescription vasodilators can cause a very frightening drop in blood pressure that, at the very least, could cause one to briefly lose consciousness and fall.

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Dietary supplement adulteration with prescription drugs: Is it really a problem of DSHEA?

ResearchBlogging.orgRebecca Skloot, journalist, University of Memphis writing professor, and author of the upcoming book, The Immortal Life of Henrietta Lacks (pre-order here), just brought to my attention this commentary by Dr Pieter Cohen in the New England Journal of Medicine entitled, “American Roulette — Contaminated Dietary Supplements.”
In the commentary, Dr Cohen remarks upon the epidemic of adulteration of herbal and non-herbal dietary supplements with undeclared prescription drugs or unapproved drugs:

In July 2009, the FDA expanded its alert to include 75 tainted weight-loss products that contain undeclared medications. Analyses by the FDA have found the stimulant sibutramine in weight-loss supplements at levels amounting to three times the maximum recommended daily dose. Several of the unapproved anorectic ingredients detected in dietary supplements have been linked to serious adverse events: rimonabant to suicide and fenproporex to both addiction and suicide. The inclusion of furosemide and other diuretics in some of these supplements may result in dehydration and hypokalemia; other contaminants, such as benzodiazepines and antidepressants, mask the side effects of stimulants while conferring an increased risk of dependence. Some weight-loss pills, including many from Brazil, combine multiple medications in a single formulation. . .
. . .Recently, unscrupulous manufacturers have made it more difficult for the FDA to detect undeclared ingredients by incorporating pharmaceutical analogues into their products. Analogues are created by modifying the original chemical structure of a compound — for example, by adding a hydroxyl group. It is suspected that these analogues are developed to evade detection by the FDA, making the products more difficult to regulate, and to reduce the risk of patent-infringement lawsuits. A recent analysis showed that more than half of 26 supplements marketed for the enhancement of sexual function contained analogues of phosphodiesterase type 5 inhibitors.

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FDA Public Health Advisory: Serious liver injury, pulmonary embolism with steroid-containing body-building supplements

American Cellular steroid products.jpgWe’ve spoken here every few months about so-called natural dietary supplements being adulterated with prescription drugs used for similar indications. The most common of these of late have been erectile dysfunction supplements which have been repeatedly found to contain the active compounds present in prescription E.D. products such as Viagra and Cialis.
The latest public health advisory from the US FDA concerns what appears to be a much more serious case of adulterations, this time with steroids in body-building supplements marketed as containing “steroid-like” compounds:

The FDA is notifying the public about new safety information concerning products marketed for body building and increasing muscle mass. The FDA has sent a Warning Letter to a manufacturer of body building supplements that claim to contain steroid-like ingredients, but in fact contain synthetic steroids. The products named in the Warning Letter are marketed by American Cellular Laboratories, Inc., and include “TREN-Xtreme,” “MASS Xtreme,” “ESTRO Xtreme,” “AH-89-Xtreme,” “HMG Xtreme,” “MMA-3 Xtreme,” “VNS-9 Xtreme,” and “TT-40-Xtreme.”
The FDA has received reports of serious adverse events associated with the use of these products and other similar products. Products like these are frequently marketed as alternatives to anabolic steroids for increasing muscle mass and strength and are sold both online and in retail stores. They are often promoted to athletes to improve sports performance and to aid in recovery from training and sporting events. Although products containing synthetic steroids are frequently marketed as dietary supplements, they are NOT dietary supplements, but instead are unapproved new drugs that have not been reviewed by the FDA for safety and effectiveness.
Adverse event reports received by the FDA for body building products that are labeled to contain steroids or steroid alternatives involve men (ages 22-55) and include cases of serious liver injury, stroke, kidney failure and pulmonary embolism (blockage of an artery in the lung). [emphasis mine]

Here is the consumer FAQ from FDA and here is the actual warning letter to the manufacturer. For those readers working in this research area, the warning letter lists the IUPAC names of the actual compounds found in each supplement.

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Sage advice?: NC to join 13 states in outlawing Salvia divinorum

ResearchBlogging.orgSalvia divinorum (Salvia, Magic Mint) is a plant used for entheogenic purposes by the Mazatec people of Mexico. A relative of the common garden plant “scarlet sage” (Salvia splendens), S. divinorum contains several hallucinogens that include salvinorin A, the first non-nitrogenous agonist known for kappa opioid receptors (KOR).
I had known of salvinorin A since a highly-cited 2002 Proceedings of the National Academy of Sciences paper by Bryan Roth, Richard Rothman and colleagues (full text here). At that time, I had read several anecdotal reports (that I cannot locate now) that the hallucinations rendered by Salvia ingestion or smoking were so bizarre and disturbing that 8 of 10 first-time users declared they would not use it again. Hence, I never really thought that Salvia would become much of a public health problem or be embraced by recreational hallucinogen enthusiasts.
However, just Google “Salvia” and take a gander at the ads on the right sidebar.
I’m still not certain if Salvia is enough of a public health problem to warrant legislation but we just learned this week that North Carolina will join 13 other US states in criminalizing possession and use of the plant or extracts made thereof:

A bill that would outlaw the psychoactive herb Salvia divinorum has passed the state Senate, prompting consumers to rush to buy it legally.
Senate Bill 138, sponsored by Sen. Bill Purcell, D-Laurinburg, would prohibit the “manufacture, sale, delivery, or possession” of Salvia divinorum. The law calls for a fine for the first two offenses and misdemeanor charges for subsequent offenses. Purcell stressed that North Carolina’s law would not be as strict as those of 13 states, which made Salvia divinorum a drug on par with heroin.

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