New blog home, same old story: dietary supplement adulteration with prescription drugs

If you are new to this blog, you should know that our laboratory and collaborators work on all aspects of physiologically-active compounds from natural sources – plants, fungi, bacteria, marine organisms, etc.

So, I am equally interested in prescription drugs and herbal or non-botanical dietary supplements. There are still some products on the shelves of health food stores that can actually provide health benefits if manufactured properly and taken in high enough doses.

However.

A common practice by unscrupulous supplement manufacturers is to add prescription drugs, or close structural relatives, to their herbal product to make it appear to the consumer that their product has beneficial effects.

In the last two weeks, the US FDA MedWatch program has announced two voluntary product recalls for dietary supplements adulterated with undeclared prescription drugs.

Another in a long litany of erectile dysfunction products boosted with compounds like those found in Viagra or Cialis comes to us from Vialipro by Good Health, Inc.:

Good Health, Inc. is conducting a voluntary recall after an FDA lab analyses found that the product tested from certain batches of Vialipro contain Sulfoaildenafil, an analogue of Sildenafil, an FDA-approved drug used as treatment for male Erectile Dysfunction (ED) making this product an unapproved drug. The undeclared ingredient may pose a threat to the consumer because the interaction of the analogue with some prescription drugs (such as nitroglycerin) may lower blood pressure to dangerous levels. Consumers with diabetes, high blood pressure, high cholesterol, or heart disease often take other prescription drugs.

The Vialipro product website is dead as of the time of this writing.

Such practice with this product class is extremely sophomoric: the FDA has had a testing program running for several years to detect these compounds in male sexual enhancement products. The FDA hasn’t updated their consumer information page since February, 2009, but this guide lists a large number of herbal products identified since 2004 as having prescription, phosphodiesterase-5 inhibitors in them.

The practice is simply disingenuous and damages the reputation of botanical supplement manufacturers (and botanical researchers) who are trying to play by the rules and rigorously study these products.

Case two comes courtesy of J&H Besta Corporation and their Joyful Slim/Slim-30 “Natural Herb for Weight Loss”:

FDA lab analysis of this herb supplement was found to contain the undeclared drug, desmethyl sibutramine, an FDA-approved drug used as an appetite suppressant for weight loss. Sibutramine is known to substantially increase blood pressure and/or pulse rate in some patients and may present a significant risk for patients with a history of coronary artery disease, congestive heart failure, arrhythmias or stroke.

The Joyful Slim website is still live (because they sell other products) but contains this ironic image:

A reason to shop from them is that they let you know about product recalls? Well, I guess that's a nice consumer feature. (From joyfulslim.com on 27 July 2010)

The FDA press releases to which I’ve linked (1, 2) contain information for the consumer on returning the products for refund and reporting any adverse reactions associated with product use.

This is cheating, my friends, and these are only the cases that are detected by the FDA. These incidents make me wonder just how many cases of reported dietary supplement efficacy are due to physiologically-active adulterants – the abundance of clinical trial failures of well-characterized, chemically-qualified herbal supplements may speak to this very issue.

GAO report on dietary supplement flaws released today in Senate hearing

Regular readers know that I hold equivocal views of the broad area of dietary supplements, particularly botanical supplements. On one hand, I have seen some great new compounds come from the systematic investigation of herbal and fungal concoctions to the point that 25% of prescription drugs are derived from natural products. On the other hand, some corners of the dietary supplement industry are little more than turn-of-the-last-century snake oil operations, with offenses so egregious that even their own trade associations try to distance themselves from those who adulterate, mislabel, and misrepresent their wares.
Just use the search box in the left sidebar and search this blog for “adulteration” to get a flavor for some examples (here, I’ve done it for you). Here’s one I haven’t gotten to that I just found thanks to the article mentioned below: the May 1 FDA consumer warning (but not recall) on Vita Breath supplement (for plumb fresh breath!) because it contains 10,000 times the lead content permitted in candy.
In today’s New York Times, Gardiner Harris gives us a preview of a report from the US Government Accountability Office (GAO) that will be presented to a Senate hearing in preparation for an overall plan on US food safety.

Nearly all of the herbal dietary supplements tested in a Congressional investigation contained trace amounts of lead and other contaminants, and some supplement sellers made illegal claims that their products can cure cancer and other diseases, investigators found. . .
. . . Senator Herb Kohl, a Wisconsin Democrat who will preside over Wednesday’s hearing of the Senate Special Committee on Aging, said that while improvements had been made in recent years in the oversight of supplements, “the F.D.A. needs the authority and tools to ensure that dietary supplements are as safe and effective as is widely perceived by the Americans who take them.”
Among the witnesses at the hearing will be Dr. Tod Cooperman, president of ConsumerLab.com, a company that has tested over 2,000 dietary supplements made by more than 300 manufacturers and has found that one in four have quality problems. According to Dr. Cooperman’s written testimony, the most common problems are supplements that lack adequate quantities of the indicated ingredients and those contaminated with heavy metals.

Go read and draw your own conclusions. I’ll look forward to seeing the whole report.
P.S. – I may be a little punchy today after a few days of grant reviews but I love that the Senator from Wisconsin is named “Herb.” In fact, Senator Kohl has been a big supporter of the Wisconsin ginseng industry. And Steve Mister, president of the trade group Council for Responsible Nutrition, is referred to as Mr. Mister. I can only think of this.

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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Update: Rocky Mountain High and the Serious Side of Colorado Medical Marijuana

Update: New ScienceBlogs colleague, Sharon Astyk at Casaubon’s Book, brought my attention to the fact that this local southern Colorado story has been picked up by CNN.
Although I originally wrote this post rather tongue-in-cheek, some scientific evidence has accumulated for the benefits of cannabis in neuropathic pain, cancer pain and nausea, as well as muscle spasticity in multiple sclerosis. For what appears to be a subset of individuals, marijuana is superior to prescription drugs in terms of efficacy and side effect profile. Equivocal results with a standardized cannabis extract oromucosal spray product have just been reported in this review.
In 2000, Coloradans voted to approve Amendment 20 to the state constitution which permits dispensaries to provide marijuana to up to 200 approved patients. This cap has since been lifted, leading to a sharp increase in medical marijuana use in the state.
Patients enroll with the Colorado Medical Marijuana Registry of the Colorado Department of Public Health and Environment (four-page PDF description here, forms here). As of 31 August 2009, the state reported that 14,377 patients hold registry cards; consistent with the known clinical efficacy of marijuana, the most commonly approved use is for muscle spasms, representing 29% of approved users.
As one might suspect, marijuana dispensaries of various sorts have sprouted up all across the state. With regulation developing slowly, some resemble glorified head shops while other are sterile clinical offices. As a result, Westword, the local independent weekly, has enlisted two dispensary reviewers who are each state-certified medical marijuana patients. Westword’s Joel Warner wrote in greater detail back in February about the literal Wild West of Colorado’s medical marijuana industry.
An even more unclear area is who is actually authorized to grow cannabis to wholesale to dispensaries. Currently, one applies to be a “care-giver” but one is only a care-giver if a registered patient lists one as such – an odd chicken-or-the-egg arrangement. In late October, the state ruled that care-givers/growers must do more than provide cannabis; they must also provide supportive medical or social services. A hearing had been scheduled for this Wednesday, 16 December, to repeal this supportive care stipulation but the CDPHE has now indicated the hearing is postponed.
So, the state of medical marijuana in Colorado is very much in a state of flux.

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Is Alexa Ray Joel’s “homeopathic overdose” possible?

Alexa Ray Joel, the daughter of Billy Joel and Christie Brinkley, was hospitalized Saturday with what I originally thought was an overdose of some type of sedative.
However, today’s Newsday and MTV are reporting that the family is calling this an overdose of a homeopathic medication called Traumeel. Traumeel is manufacturer by an Albuquerque-based company called Heel USA, a company founded by a German physician in the 1920s.
If Traumeel is truly homeopathic, there is absolutely no way this product could have caused Joel’s hospitalization.
If you are new to our blog, you may not know the different between herbal medicines and homeopathic remedies. Herbal folk remedies are actually the source of some commonly used pharmaceuticals. And like drugs, herbs have the potential to have a therapeutic effect in direct proportion to the dose given. The more herb, the more likely a benefit – or side effects – may be observed.
Homeopathic remedies, however, have nothing to do with herbal medicines. In fact, the basic principles underlying their use are diametrically opposed to everything we know about physics, chemistry, and biology. They are the remnants of a pseudoscientific practice developed in the 1800s whereby it was deemed that a substance which produces effects similar to an illness can be diluted out (or “potentized”) to create a remedy that might treat that illness. Hence, extremely dilute ipecac (which is used to induce vomiting) might be used homeopathically to treat disorders that involve vomiting.
The primary reason people get confused between herbal/botanical medicines and homeopathic remedies is that both are often derived from similar plant materials.
However, homeopathics differ in one critical respect: they are often so dilute that they contain not a single molecule of the original starting material. Homeopathic remedies are essentially water that is sold at even more exorbitant prices than bottled drinking water.
An excellent and approachable overview of homeopathy can be found in this 1996 article (free PDF) in the American Journal of Pharmaceutical Education by Dr W Steven Pray of Southwestern Oklahoma State University’s School of Pharmacy. I have used it for over 10 years in teaching students and educating the public.
So let’s look at the composition of Traumeel, purported for used as an anti-inflammatory agent for musculoskeletal injuries. Traumeel comes in several dosage forms, including one for injection, but let’s look at the tablets, especially since the New York Daily News reported reports a 911 call that Joel “had taken some pills”:

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How to report in vitro cancer studies: maitake mushroom extract doesn’t “fight cancer”

ResearchBlogging.orgEarlier this week, I saw one of the best treatments of a misinterpreted story that has me thinking about how all news outlets should report in vitro laboratory studies.
Only thing is that it didn’t come from a news outlet.
It came instead from a brainwashing site run by those medical socialist types – I am, of course, speaking of the UK National Health Service and their excellent patient education website, NHS Choices.
You may recall reading in the popular dead-tree or online press that investigators from New York Medical College in Valhalla published in British Journal of Urology International about maitake mushroom extract killing bladder cancer cells. The most widely cited reports came from the UK Daily Mail by Tamara Cohen entitled, “Mushroom ‘shrinks cancer tumours by 75 percent,'” and “Cancer Cure: Mushrooms Can Shrink Tumors,” by Jo Willey of the UK Daily Express.
Well, NHS Choices took a look at the study and detailed how the mushroom extract was only used on bladder cells in culture. Throughout their review and in the conclusion that follows, they specifically took to task the story in the Daily Express:

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More naturopathic nonsense in Ontario

As we mentioned earlier this week, a brouhaha has erupted north of the border (or just a bit east for our Detroit-area colleagues) whereby graduates of Canada’s two naturopathy schools may be given drug prescribing rights by the Ontario legislature. Editor-in-chief of the Skeptic North blog, Steve Thoms, put up this detailed background in “Fake Doctors with Real Drugs,” at the JREF Swift blog:

Bill 179 was introduced in the spring of this year as a way of expanding scope-of-practice for health care professionals in Ontario, including (but not limited to) nurses, midwives, pharmacists and radiologists. Such an expansion was recommended by the Health Professions Regulatory Advisory Council (HPRAC), and this organization also recommended further that naturopaths be granted prescription rights. The Bill would have aimed to do this by amending a previous act of the Ontario Legislature, the Naturopathy Act, 2007. In this act, a “naturopath” is defined simply as someone who graduated from one of the two naturopathic colleges in Canada (neither of which are affiliated with any Canadian accredited university, and have extensive courses in homeopathy, Traditional Chinese Medicine, and colonic hydrotherapy). After the first reading of the bill, the HPRAC’s recommendation for naturopath prescribing rights were soundly rejected. Before the bill’s second-reading, a coalition of naturopathic associations organized a write-in campaign to put the naturopathic amendment back into the bill, and they were successful on Oct 20.
The bill itself has gone through two readings so far, and the third and final reading has been ordered (but not yet scheduled). The current session of the Ontario legislature will likely be over in less than a month, so the bill will likely be presented for it’s third reading, at which point it will be enshrined in law. Then naturopaths, homeopaths, acupuncturists, and Reiki practitioners will have the right to prescribe anti-inflammatory, anti-biotic, and narcotic (just to name a few) medications.
Supporters of the naturopath expansion have framed this issue in two disingenuous and/or problematic narratives: one of freedom, and one of access. The former is being presented as allowing Ontario citizens the freedom to seek out alternative health modalities and freedom for naturopaths to prescribe medications that they need to; the latter as a way of dealing with the doctor shortage. Both of these arguments are deeply concerning, because a) there is no law in Canada that prohibits citizens from seeking alternative treatments, and b) if a person who requires legitimate medical attention and feels they are unable to see a doctor in a timely manner, they are far more likely to seek out alternative avenues, potentially finding a dangerously-untrained and under-qualified naturopath.
This is not a matter of freedom of choice, nor is it a matter of helping deal with the doctor shortage. This is about granting political legitimacy to a pseudo-science when it’s practitioners are unable to gain legitimacy the way that conventional medicine does: through science, evidence, testing, and peer-review. Most people are not skeptics, and when they hear “Naturopathic Doctor,” many are just as likely to see the holder of title as just another primary care provider. Think about that when your mother needs heart medication, or your nephew gets an ear infection.
Defeating a bill in its third reading is rare, but not impossible. I’m asking for all Swift readers (especially the Canadians and Ontarians) to email the Ontario Premier, Dalton McGuinty, and (dmcguinty.mpp.co@liberal.ola.org), as well as the Minister of Long-Term Health and Care, Deb Mattews, (dmatthews.mpp.co@liberal.ola.org). It would also be wise to CC the same email to Andrea Horwath, leader of the New Democratic Party (ahorwath-qp@ndp. on.ca) and Tim Hudak, leader of the Progressive Conservative Party (tim.hudakco@pc.ola.org). The bill is under review by the Standing Committee on Social Policy (for a complete list of the members of the committee, click here), so Ontario residents would do well to email them as well. Remember to CC all correspondences, so that everyone knows who else is reading what.

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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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“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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