Friday, February 24, 2006

Nomination for Best Medical Journalism of 2006 (thus far)

I'm in the midst of reviewing grant applications for a US research funding agency and have been pretty frazzled and distracted from blogging. I couldn't stomach writing a post on this week's press citing mostly negative outcomes from a trial of glucosamine and chondroitin in patients with mild arthritis pain, the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT).

However, most journalists missed the boat on the trial because few read more than the largely negative press release from the New England Journal of Medicine. A more insightful analysis, such as that done by Jennifer Corbett Dooren in the Wall Street Journal, reveals that the subgroup of patients with more severe knee pain actually had significantly more pain relief than those given placebo. In fact, Ms. Dooren's article was one of very few in the US that led with the positive findings. (If you don't have access to WSJ, e-mail me and I can send you a link from my personal account that's good for 7 days).

Anyway, I mention this article mostly because I'm growing tired of sloppy medical journalism. The tendency these days is for writers to increasingly rely on journal press releases and just parrot the findings without doing their own critical analyses. Some have raised real concerns about the motivation of NEJM in spinning the glucosamine/chondroitin results to minimize the positive news. But, to get the complete objective story you'd actually have to read the article yourself, or rely on journalists like Jennifer Dooren who are among the rare exceptions.

With that said, I want to bring readers to the attention of two phenomenal posts this week by Kathleen Seidel at Neurodiversity and physician-scientist blogger, Orac, in his now fully-functional new digs at the ScienceBlogs brand of Respectful Insolence.

The Seidel/Orac brain trust is my nominee for best medical journalism of 2006 (thus far).

This tag team has brought us an exhaustive analysis of new claims by mercury-autism advocates and the unethical and dangerous proposal to use Lupron (leuprolide) to treat children with autism. Having spent half of my postdoc in a division of endocrinology was enough for my bullshit-detector to go haywire when I first learned of the idea to use a GnRH agonist chronically, known widely as "chemical castration," to treat autistic children.

Key to their analyses is the strong, well-supported proposal by Kathleen Seidel that lazy journalists are complicit in the promotion of outrageous, unscientific claims of so-called experts who lack the credentials to be so considered.

Like many scientists, I used to grow glassy-eyed at any of the pseudoscientific and baseless claims that autism is due to mercury poisoning from thimerosal in vaccines, that autism could be cured by chelation, etc., because I thought these were just wacky claims from a fringe element. What I've learned is that relatively influential and financially-motivated persons in the autism community are creating medical danger for hundreds of thousands of children by preying on rightfully concerned parents who are swayed easily by emotional, but non-scientific, arguments.

If you've ever blown off the mercury-autism story as that of "just a bunch of crazies," I urge you to take 20 minutes today and first read Kathleen's detailed background, then Orac's medical deconstruction of the bizarre world of a dangerous, rogue physician/lawyer team.

As I've seen on a bumper sticker: "If you're not mad, you're just not paying attention."

Tuesday, February 21, 2006

Hoasca, dimethyltryptamine (DMT), and the US Supreme Court

ADDENDUM 17 March 2006
SUMMARY FOR NEW READERS: Thanks to Daily Grail for referring to this post. The bottom line is that significant pharmacological concern exists for taking Hoasca/Ayahuasca together with the SSRI class of antidepressants. The biochemical basis of this concern is discussed below in my hypothesis to account for a published case report of a fatality associated with Hoasca use.

Much of humankind's experience with pharmacologically-active natural products has been through the mind-altering effects of plants used in religious ceremonies.

Today, the US Supreme Court upheld a decision to permit a New Mexico sect of a Brazilian religious order to continue using an herbal hallucinogenic tea for religious purposes despite the fact that the tea contains a US DEA Schedule I controlled substance (N,N'-dimethyltryptamine). Schedule I substances are classified as compounds that have no recognized medical value in the United States.

I had heard that the Supreme Court was moving toward support of faith-based groups, but this one was a surprise to me, particularly given the unanimous decision in favor of the defendants (8-0 since the recently-confirmed Justice Alito could not participate in rendering the decision).

The precedent for protecting these rights is the 1993 Religious Freedom Restoration Act.

The Wikipedia entry on the case is pretty accurate and a great reference on the political side of this story. But let's address the fascinating pharmacology of this ethnobotanical hallucinogen (ethenogen).

The Hoasca hallucinogenic tea, more appropriately called Ayahuasca, is made from stems of the vine Banisteriopsis caapi together with the leaves of Psychotropia viridis (in Brazil, Peru, and Ecuador) or Diplopterys cabrerana (in Ecuador and Colombia). The latter two plants contain the hallucinogen, DMT, a serotonin analog that stimulates 5-HT 2A receptors similar to LSD. However, DMT alone would normally be very quickly metabolized in the liver by monoamine oxidase A (MAO-A) such that little of the compound, if any, could get to the brain.

Hoasca or Ayahuasca
The key plant is B. caapi which is not hallucinogenic on its own. Instead, B. caapi contains beta-carboline compounds that inhibit the liver's ability to destroy the DMT. Most important among these is a compound called harmine, a well-characterized MAO inhibitor. In pharmacology, one would say that harmine potentiates the hallucinogenic effect of DMT. As a scientist, I am in awe of the South American cultures that discovered this concotion long before we had HPLCs and mass spectrometers.

The bottom line is that without harmine, one does not hallucinate from ingesting DMT orally. But before my counterculture friends start converting to the Santo Daime or Uniao do Vegetal, there are some very serious considerations.

Although hallucinogens are rarely associated with fatal events directly, there has been at least one well-documented death associated with this herbal concoction. The cause of death was undetermined in this case, but one might hypothesize a scenario whereby the cause related more to the MAO inhibitor part of the herbal cocktail than to the hallucinogen itself.

MAO does not exist in our livers (and in the mitochondria of our neurons) to allow us to experience hallucinations. The primary purpose of MAO is to destroy blood pressure-raising chemicals from both our diet and our own nervous systems that, if allowed to accumulate, could kill us. One of the dietary forms of these chemicals is called tyramine.

If your MAO is inhibited and you eat foods rich in tyramine (such as aged cheeses or red wines), you could conceivably go into a hypertensive crisis and die.

A Modern Confounder of Risk-Free Hallucinations
But, there is a modern contributor to this well-known drug-food interaction that might be underestimated. Many antidepressant drugs inhibit another liver enzyme that breaks down's called CYP2D6. Many antidepressant drugs known as SSRIs act to inhibit CYP2D6 and some of these could thereby prolong the MAO inhibitory action of harmine.

So, let's say you're battling with the dog of depression and taking an SSRI like Prozac or Paxil and you're fond of red wine and cheese. Not uncommon, especially in academia.

But let's say you also get religion...the South American kind...the kind that uses Ayahuasca in their Nativity celebrations. You take a batch of the ceremonial tea and the harmine inhibits DMT metabolism by MAO - good thing: religious hallucinations.

However, the SSRIs you're taking also inhibit the liver's breakdown of harmine by CYP2D6. It's possibly that you might experience longer or more intense hallucinations than someone not taking an SSRI. Not a problem until you reach for the 1990 Chateau Montrose and some nicely aged pecorino (I know it's a stretch but bear with me..there's only been one reported death thus far). Massive amounts of tyramine get into your bloodstream, speeding your heartrate while also causing your blood vessels to constrict. As pathologists are fond of saying, this is a situation that is incompatible with life.

In fact, this was not such a far fetched scenario 20 years ago since MAO inhibitors were used widely as antidepressant drugs (and still are in some very serious cases) and patients would be given a long list of foods to avoid for this very reason.

This issue can be even more complicated since some of us are already set up genetically to be slow or fast metabolizers of drugs like harmine. CYP2D6 activity varies quite a bit across ethnic groups and individuals, with some people being much more sensitive to harmine overload. Not surprisingly, the high priest-equivalent in the Uniao do Vegetal faith gets to know fellow worshippers well enough to provide them with the proper dose of hallucinogen based upon past experiences.

Yes, you've got it: ancient South American religions knew about pharmacogenetics long before we knew the structure of DNA.

So, the health danger of this hallucinogenic tea is real, albeit rare. But isn't it surprising that an inappropriate mix of ancient and modern culture and medicine could theoretically lead to fatal outcomes for a practice meant to bring one closer to their god?

Hearty congratulations to the faithful who have won this battle, but caution to those wishing to exploit this win for recreational purposes.

Another Southerner takes on homeopathy

Now that the Daily Telegraph crossword brouhaha has died down, I guess I'll have to earn my hits with some new content.

Until then, let me point you to a blog I've missed completely until recently, Science, Shrimp, and Grits, and their lovely, illustrative post, "Freshman Chemistry Takes on Homeopathy."

After reading the post, even the most staunch supporter of homeopathy has to ask if they are fooling themselves.

I'll be sending their post to both Ode Magazine and Utne.

Monday, February 20, 2006

Welcome UK Telegraph Crossword Society!

For those of you still trying to solve this past week end's Telegraph crossword, the other word for terra sigillata is Samian ware.

According to the Wikipedia entry,

"Samian ware is a kind of bright red Roman pottery also known as terra sigillata. It is similar to the earlier Arretine ware and both types are attempts to copy more expensive metal originals. Because of this they display skeuomorphic characteristics. It was first made during the first century AD and production ceased around the mid third century.

Samian has nothing to do with the island of Samos but was once thought to have originated there, and the name has stuck, at least in British usage. It may also be derived from the Latin verb samiare, to polish. It can be identified from its pinkish or orange fabric and a distinctive smooth red surface created by dipping the unfired pot in slip before putting it in the kiln."

For regular readers looking for some scientific coverage of natural product drugs and botanical medicines, you'll see that my SiteMeter had me happily sidetracked this weekend learning all about the geography of the United Kingdom. Over 400 visits from the UK, all searching for 'terra sigillata' since 8 am GMT on Saturday, have raised my cumulative British country share from under 5% to well over 20%.

Turns out that terra sigillata was the clue for the Saturday Daily Telegraph crossword and we've been doing well enough here to get on the first or second pages of Google search results. (Makes me think it might be time to start accepting AdSense adverts for ceramic arts supplies).

Of course, "superb weblog for objective information and commentary on natural product drugs and botanical dietary supplements," was too long to be the right answer. So, with a little searching and charming comments from British readers, we learned that Samian ware is another name for the bright red glaze on ancient pottery.

Thank you, wise British readers, for coming over to take a look at our site. Botanical medicines and homoeopathics are very widely used in the UK and I'd be grateful for any input you might have on your own personal experiences, from, "it's all crap," to, "I have no idea how homoeopathy could possibly work, but it does for me." I also have deep respect for the British pharmacology community since 1988 Nobel laureate, Sir James Black, discoverer/designer of cimetidine and propranolol, spoke at my university commencement proceedings in 1985.

Moreover, this experience been a great geography and history lesson for me to teach our 3-year-old girl since my wife is long-descended from English and Scottish roots, with each side of her family moving to the southern US in the 1680s. A great many of our town and state names, north and south, are copied from the Motherland and we hope to travel over once she is of school age to teach her about her heritage. Not to mention that her Dad has a penchant for fine British ales!

I've also had some great comments on the earlier post, particularly from "crazy grannie" and others who had never heard of blogs before. You can see this in the thread of my previous post but I wanted to reproduce this lovely comment here:

"Abel - I think I just messed up a blog - have only just discovered what they are thanks to you and a grandson hastily summoned over internet to check you're not a VIRUS whatever that is - he says OK. So will try again - just to say thank you SO much as I have now completed my GK crossword and like all the others live in hope of £2oo - not a lot you may think but it is to me and it is the thrill of the hunt! The name Abel Pharmboy will ever be dear to me as providing me with assistance in timewasting but so amusing hobby and in teaching me yet another weird modern activity. From a new blogger Cheers!!as i raise a triumphant glass of Amontillado in your honour!!"

And cheers to you, anonymous commenter, as I raise my glass of Graham's LBV Port in return!

Sunday, February 19, 2006

Quick question for British readers

In the past 36 hours, I've had a spike of traffic from the UK, all mostly via Google searches for 'terra sigillata.' This little ol' blog usually only gets about 40 hits per day, and even fewer on the weekends, but was well over 300 yesterday.

Although my header notes that I don't discuss pottery, this early post details the overlap and distinction between the potter's terra sigillata and the ancient medicinal form of the clay that I took to name this blog.

I suspect that you weren't searching for issues on medicines derived from the Earth. Was there some major pottery or clay crafting conference in England this weekend?

I'd appreciate greatly any enlightenment from my British readers...cheers!

Saturday, February 18, 2006

Diluting a Disease?...or Deluding Yourself?

Dear Editors of Print Magazines to which I subscribe,

I really, really appreciate your coverage of liberal issues that speak to the core of my being and the values I am trying to instill in my young daughter: equality and tolerance, the fight against racism and poverty, the mysteries of love and the power of music and the written word.

However, when writing about science and medicine, I implore you to be more responsible. Equip your staff and interns with some training in how to evaluate medical topics, alternative medical approaches, and evidence-based medicine, with emphasis on the word "evidence." I am open to considering anything new that challenges existing dogma, but I won't risk my health without some evidence.

With love and admiration otherwise,
Abel PharmBoy


Regular readers may recall my objection a few weeks ago to Ode Magazine's article on the potential of homeopathic remedies to combat the human H5N1 form of avian flu, citing cure rates from the homeopathic literature following the horrific 1918 influenza epidemic.

While fighting off a migraine from reviewing research grant applications, I ventured out on this snowy/rainy Saturday to our snail-mailbox and was happy to see my usual issues of Mother Jones and Utne that invariably arrive on the same day. As a white-collar professional removed only one generation from the Northeastern, blue-collar factory culture, I still resonate with the fight against worker exploitation and the real-life Mother Jones' fight for rights among unionized labor, especially coal miners in the East and in Colorado ("Pray for the dead, and fight like hell for the living."). Ah, Utne has a nice article on Billy Bragg and his "songs of passionate anger at injustice." Cool.

But on the cover of this March/April issue of Utne is an article on how homeopathy could stop the avian flu. Okay, okay, I'm willing to forgive Utne for republishing the article from Ode - after all, much of Utne is derived from the culling the best of the alternative media and the Ode homeopathy article was quite widely-publicized and demonized, both in the blogosphere and in their own 'Letters to the Editor" section.

But, no, the Utne article is an original: "Diluting a Disease: Could Homeopathy Stop the Avian Flu?" This brand-new article, covering much of the same ground as the earlier Ode article, is authored by Morgon Mae Schultz, an Utne intern who, best as I can tell from Google, had been a journalism student at the University of Minnesota and editor of their student publication, The Wake.

Given the admirable stature of Minnesota higher education and my personal respect for Prof PZ Myers (although he is at the far western campus of Morris and can't be held responsible for what happens in the Twin Cities), I was sure that Schultz would be rigorous and fact-based in cautioning Utne readers about relying on homeopathy for much of anything. In fact, even herbal medicine trade groups have declared quite wisely and responsibly that no dietary supplement company should even claim remotely that their products would be useful in an avian flu pandemic.

Unfortunately, the aspiring U of M journalist fell prey to the same claims of 1920s homeopathic literature claiming a 99% survival rate among 1918 flu-stricken patients, as opposed to 70% for conventional medical care. Schultz even interviews a homeopath and describes the ritual of dilution and succussion (vigorous shaking) to produce a "remedy." "No one knows exactly why this works, but homeopaths posit that water retains the energy of the substance and delivers a message to the body."

Yes, and that message is to keep both hands on your wallet.

But what struck me was the journalist's assumption that "this works" while also blowing off the mystery of the mechanism. Moreover, the article claims that "homeopaths...already have the ability to study the disease in patients without worrying about which strain of the virus is the culprit...Best of all, homeopathy is about strengthening the body instead of targeting the bug, so patients don't become unwitting vessels for a mutated virus."

Well, call off the CDC - no more worries about tracking and genotyping Asian flu viruses each year to know what strains to use in vaccine generation. As for strengthening the body, one needn't worry about getting proper balanced nutrition, plenty of sleep, and exercising general handwashing hygiene during the flu season. One needs to just rely on a homeopathic remedy.

But nowhere in the article is mention of what specific homeopathic remedies would be used against avian flu. Why wouldn't one make a 30C dilution of the H5N1 bug if that were how homeopathy really worked?

In fact, why not just drink regular tap water as your homeopathic remedy??? Think about it: the molecules of water we drink today could have been the urine of Alexander the Great or the industrial effluent of Monsanto. Today's water has had diluted in it over thousands and millions of years almost every infectious organism, toxic metal or organic substance (natural or synthetic). Hence, it should be a remedy for every illness created by every solute ever dissolved amongst its molecules.

Let's say that I am willing to admit that homeopathy might work, albeit through some unknown physical mechanism that I cannot explain. What would follow is that drinking tap water should have every potential remedy in it that I could ever want, to cure everything from multiple chemical sensitivities and mercury-induced autism all the way to the diseases I might incur from eating anything from gold mine tailings to my own feces.

Oh, I forgot..drinking tap water would not create revenue for homeopathic practitioners.

As so eloquently stated by the late Gilda Radner's character, Roseanne Roseannadanna, "Never mind."

Thursday, February 16, 2006

28th Meeting of the Skeptics' Circle now live

Eh Nonymous at Unused and Probably Unsafe has just posted the the 28th meeting of the Skeptics' Circle.

As my blogging mission develops, I'm realizing that I can do more than simply educate and inform. I can also do my little part to defend and protect the scientific method and help to restore the basic scientific competence that has so badly deteriorated in the US, not just among the public but even within our advisory and funding agencies.

Hence, I put up for consideration my critique on the NCCAM-supported, negative saw palmetto trial in BPH that appeared in last week's NEJM.

Many thanks to Eh Nonymous for giving me a shot and including me among such learned company.

Wednesday, February 15, 2006

Grand Rounds and a wee bit o' housekeepin'

First, make sure to get over to Intueri for yesterday's Grand Rounds 2(21). The Valentine's-influenced personal ad presentation of picks is worth a visit in itself. Of course, always great to read the best medblogging of the week.

Second, did a bit of housekeeping on my profile to emphasize further the stature of my nym-sake, John Jacob Abel. When molecular biologists look down their noses at us pharmacologists, I remind them that a pharmacologist founded the JBC. I also moved a link to my e-mail to the front page profile in case any lurkers have suggestions for topics they might want to see here.

Third, I added a disclaimer earlier today that can always be referred to in the new "Welcome New Readers" section. It's all common sense, but the assumption of personal responsibility for one's actions in the US is not all that common.

Finally, the long-awaited move of Orac's Respectful Insolence to ScienceBlogs is now complete. I've updated the link in my blogroll to the right but it seems that there were some template and feed problems this week. Since my stats show that about a third of you get to me via Orac referrals, you probably already know this. For those of you who don't, Orac is only the second addition to the "Medicine" section of ScienceBlogs, joining Dr Tara C Smith of Aetiology.

Orac is a US-based surgical oncologist who holds forth comprehensively on issues of medicine and all-around skepticism, from Holocaust deniers to extreme alternative medicine advocates. Prof Smith is an incredibly well-versed infectious disease, microbiology, and public health expert and Aetiology is a great source for facts behind flu hysteria, antibiotic drug resistance, and being a successful faculty member while also being a great Mom and wife.

Good people, good information - what more could we ask for?


As PharmMom reminds me, I am not a real doctor, nor do I play one on TV.

So what am I?

I am a PhD pharmacologist with what I hope is excellent training at the lab bench. This means that I study how new drugs work to modify physiology and pathophysiology in a manner that works toward restoring and maintaining health. We pharmacologists also devise strategies to make existing drugs more potent and selective to reduce side effect profiles. (If you're an undergraduate student looking for more information on a career in Pharmacology, check here.)

In the US, we normally pursue a 4-year university degree in some biology or chemistry discipline, then pursue combined didactic-laboratory PhD training (usually 4-7 years), often in the basic science department of a medical school. Graduate training in Pharmacology culminates in the oral defense of a 100- to 500-page research dissertation comprising the bulk of our lab studies. Most graduates then pursue a postdoctoral fellowship, or "postdoc," of loosely-mentored research under a major professor driven primarily by the freshly-minted PhD with the aim of developing skills to become a competitive, independent investigator in academia, industry, business, journalism, among other careers. Some of us do a bit of teaching, either out of love or by edict of your department chairman: I'm fortunate have a pretty decent 17-year record of educating health professional students (out of the love of it) in medicine, pharmacy, dentistry, nursing, physical therapy, public health, and medical journalism, often at the highest attainable degree of each profession.

Now to the star of our show, the official blog disclaimer:

But I have no professional qualifications for commenting on patient care or providing direct advice on clinical management of any disease. I do provide advice to my physician (MD) colleagues when solicited, but they interpret my contributions within the full framework of their extensive training in differential diagnosis and medical treatment.

What this means is that I have no business in consulting with patients directly on their drug regimens or making suggestions on the use of specific dietary supplements. While some non-MD 'practitioners' will do so independently of a primary-care doctor, I consider such behavior as a violation of professional ethics and a danger to patients. If you show up at my laboratory for an herbal consult, all I am qualified to do is put you to work in my lab.

Hence, the information I provide is for information only and is intended to protect you from the unscrupulous practices of a few unsavory alternative medical practitioners and a very few dietary supplement manufacturers who choose to practice outside the voluntary standards of their respective major trade associations.

Any advice I might provide is for educational and entertainment purposes only or, at most, to give you information to bring to your primary care physician to discuss within the context of your total medical care plan. Anyone who uses information posted on this blog for self-medication with dietary supplements independent of the guidance of a licensed health-care professional, takes personal responsibility for their decision and does so at their own risk, recognizing that they may be delaying early detection, proper diagnosis, and successful treatment of potentially life-threatening diseases.

The opinions and scientific conclusions expressed here are mine alone and do not represent the views of any funding agency, local or federal advisory panel, research organization, university, colleagues, administrators or laboratory co-workers with whom I am associated. PharmMom, PharmSis, PharmGirl, and PharmPreschooler would also prefer that you not hold them responsible for my rantings as well. I do get cranky and am well-known to bite the hand that feeds me, particularly when the body to which that hand belongs exhibits unscientific or unethical behavior.

I post as a scientist who is a caring citizen of the world to disseminate what I perceive as truth supported by factual information.

I am also the sole administrator of this weblog. The blog administrator is dedicated to open discourse, especially on controversial topics, and welcomes lively debate on issues via the comment function of Blogger. Through mutual consideration, mutual respect, and presentation of opposing views, we hope to arrive at truth. However, the blog administrator reserves the right to remove comments by and/or block access of commentors whose content is deemed inflammatory, libelous, and/or dangerous to human health. Personal attacks will only be permitted if it is deemed that the individual being targeted is operating in violation of federal, state, or local laws, particularly those related to the practice of medicine. The blog administrator reserves the right to serve as the final referee on such matters, but will seek qualified legal and medical advice where indicated.

Otherwise, let's go wild and have fun. Pharmacology is the most interdisciplinary of the biomedical sciences and the world is full of unrealized therapeutic agents that have the potential to reduce or eliminate human suffering.

I hope to learn as much from you as I can offer here in my little piece of the blogosphere.

Tuesday, February 14, 2006

Politics, religion, science, and art

I've started about five different posts since last week, but haven't really finished with any of them. The time I used to spend in the evenings musing about the world has been replaced by the joys of being a father to a marvelous 3-year-old daughter. I've found lots of new stuff to discuss in botanical and alternative medicine, but I thought I'd reflect a bit on how extreme views of any sort have tainted what is good about science and art, and even politics and religion, for that matter.

Our developmental biology colleague, PZ Myers, took some grief the other day when posting about Garrison Keillor's Prairie Home Companion show at the University of Minnesota at Morris. Prof Myers and some commentors were a bit put off by the abundance of gospel music at the show. The subsequent thread then degenerated into a discussion that was philosophically a bit over the head of this reductionist scientist. Apparently, some folks have trouble with religious values coexisting with contributions to the arts, much less the sciences.

I thought about this a little more over the weekend as I received some info on my 25th high school reunion from a small Catholic high school I attended in the Northeast. I wasn't really a terribly devout Catholic and I consider myself among the legion of tongue-in-cheek "recovering" Catholics. My sister and I were at least raised in one of the more palatable "National Catholic" offshoots of Roman Catholicism: birth control was cool, priests could marry and have children, and abortion, while obviously not encouraged, wasn't necessarily prohibited.

Anyway, PharmMom sent me to small Catholic high school more to get me out of our crappy public school system since she thought I'd have a better chance of getting into premed university programs - I chose the PhD route, of course, and it's only taken her 20 or so years to come around and forgive me for not becoming an MD. My postdoctoral advisor was fond of saying that being raised Catholic was great preparation for becoming a molecular biologist because both disciplines required belief in things that could not be seen.

The point of talking about this is that I can point to a couple of outstanding teachers of chemistry, physics, and biology at this Catholic school who were incredibly formative in developing my appreciation of the scientific method and my ultimate decision to pursue the medical side of biochemistry as a career. I'd venture to say that I'd not be where I am today without the science education I received in this Catholic school. Moreover, my class in world religions gave me a greater appreciation of other faiths at a much younger age than I would have gotten in most public school systems. As a result, I feel that I was equally prepared for college with both scientific skills and an open and tolerant worldview of cultures and religious practices that were not my own.

I was reminded further of my formative years yesterday by PharmGirl, MD, who turned me on to a USA Today op-ed by Rob Borsellino of the Des Moines Register. Mr Borsellino just returned from a trip to Italy where he encountered the old Jesus, the one that America seems to have lost.

Perhaps I was naive or completely ignorant some 25 years ago; the late 70s and early 80s were not easy or simple times for the world.

But those days did at least seem closer to a peaceful coexistence of people and ideas.

Back to pharmacology and pharmacognosy in my next post.

Wednesday, February 08, 2006

Another botanical clinical trial doomed to failure from day 1

You'd think the funding folks would learn at the NIH National Center for Complementary and Alternative Medicine (NCCAM). But, not as evidenced by the report in tomorrow's New England Journal of Medicine detailing the lack of efficacy of saw palmetto (Serenoa repens) extract in the treatment of benign prostatic hypertrophy.

Yet another well-designed double-blind, placebo-controlled trial has been doomed to failure by inadequate chemical characteriztion of the study material. Political pressure to produce a postive clinical result has bypassed the normal path of pre-requisite basic science studies, casting a shadow on what may still be a useful herbal medicine.

About 2.5 million US men use extracts of berries from saw palmetto, a low-lying, scrubby palm native to the coastal southeast from South Carolina to Florida that can also be found in southern California. A couple of small clinical trials, covered in this Cochrane review, had intimated that saw palmetto extracts can improve urinary flow in men with enlarged prostate glands, with efficacy similar to the prescription drug finasteride. Finasteride, sold in the US as Proscar, inhibits an enzyme called 5-alpha-reductase that converts testosterone to its more active form, dihydrotestosterone. As a result, finasteride has been associated with a greater incidence of sexual side effects (mostly ejaculatory disturbances) relative to saw palmetto as detailed in this meta-analysis.

No one knows for sure how saw palmetto is thought to work. Some reports suggest that it too is a 5-alpha-reductase inhibitor, but then wouldn't it be expected to produce the same sexual side effects as finasteride? No evidence exists either to suggest that saw palmetto might act as a alpha-1A adrenergic receptor antagonist, like another prescription drug, tamulosin.

In fact, no one knows the precise chemical compound(s) in saw palmetto extract that reduces prostate swelling. How then could a major US funding agency approve the conduct of a clinical trial when there was no possible way to chemically characterize the study agent? If you don't know what to look for, how do you know it's there?

Well, an advisory panel for NCCAM thinks they know. Cited in the paper was that while there are no widely-accepted guidelines on the content of saw palmetto extracts, a number of authorities have recommended that extract contain 80-95% fatty acids or 85-95% fatty acids and >0.2% sterols. Why no requirements for the presence of specific compounds with real, IUPAC names?...because no one knows the identity of the active components of this herbal extract. Would you be willing to invest what was probably $2-4 million in a clinical trial of this extract?

Not me, and certainly not with US taxpayer's money. The scientific approach would be, minimally, to design an in vitro model for markers of prostatic hypertrophy (not exactly my area of expertise) and then chemically fractionate saw palmetto extracts to find the one, two, or ten chemical compounds that had effects on these endpoints. Then, you might want to try some simple metabolism experiments (and perhaps a phase I clinical trial where these pharmacokinetic parameters are assessed before anyone in their right mind would jump full bore into a phase III efficacy trial) to be sure that any of these compounds might make it to bloodstream and the prostate in concentrations consistent with these effects when patients are given a certain dose. After all, we catabolize fatty acids for energy and the liver's cytochrome P450 drug metabolizing enzymes are likely to have first evolved to destroy plant sterols we encounter in our diet.

Instead, the authors report that NCCAM chartered an "expert advisory committee" who conducted a bidding process to find a company that would provide them with an extract that met the above criteria together with a placebo. One of my herbal industry sources close to such a bidding process for another botanical trial reported that all NCCAM cared about was whether the company would absorb the costs of providing the study material. This all but rules out any small company that might be doing excellent science and favors the herbal big-boys, narrowing the choices to two or three companies. And why worry about saving $100,000-$200,000 at most when a $3 million trial is riding on the quality of the study material?

No offense is intended toward the investigators and authors of this trial. They are all highly-qualified MDs, PhDs, and/or MPHs at one of the premier US academic medical centers and the primary author was a recipient of a highly-competitive physician-scientist career development grant called a K08. However, the investigators relied on their funding agency to procure for them the best product and one that had been well-characterized for chemical composition and biological activity. In this case, the funding agency clearly let down their grantees.

Anyone associated with drug discovery and development whether in academia or industry will tell you how extreme the guidelines are for chemical composition and purity of any drug product intended for clinical trials. Yet, NCCAM continues to fund expensive clinical trials of botanical therapies even when the chemicals purported to be responsible for biological activity(ies) are unknown. In the rush to show clinical utility, this funding agency has taken shortcuts on the basic science studies necessary to precede any clinical trial, perhaps hoping that one day they will get a positive result. Instead, they are racking up a series of high-profile failures that cast a broad shadow across all natural products research and creating public relations challenges for otherwise well-meaning herbal education and trade groups.

Only now has NCCAM revealed that they probably should fund investigations of basic science, mechanisms of action, and, be-still-my-heart, phase I pharmacokinetic trials.

Since its inception in 1992 as the NIH Office of Alternative Medicine, NCCAM has been a lightning rod for criticism of how the scientific method has been abandoned in favor of trying to show that ideological therapies work. Basic scientists in pharmacognosy and natural products chemistry were enthusiastic initially that a new funding source would be available to support their work. However, NCCAM was charged with reviewing all types of alternative therapies, from the more legitimate realm of herbal medicine to the implausible, homeopathy, for example. Review panels were stocked with individuals who had never held an NIH grant, much less with experience reviewing grant applications. An unusually high percentage of dietary supplement industry and trade group panelists infiltrated the peer-review system. In 2002, reported that just ten individual investigators held more than 20% of the NCCAM budget. I'd encourage Dr. Sampson to conduct another assessment today.

Herbal or botanical medicine holds great historical promise for the prevention and treatment of illness. In the past, we have usually tried to identify the biologically-active compounds present in herbal medicines so that doses could be established for standardized scientific products. (This principle was first recognized and appreciated in the early 1800s when the German pharmacist and chemist Serturner first isolated morphine and codeine from the poppy, Papaver somniferum.).

But, if you jump into a clinical trial without knowing what you're testing, how can you have any confidence that a positive or negative outcome is meaningful? Or reproducible?

Only time will tell if NCCAM's newfound embracing of mechanistic, basic science studies will improve the likelihood of success in clinical botanical trials. I encourage my basic science colleagues to answer the call if they are asked to serve on NCCAM grant review panels.

The only way to be sure that solid science is done is to have solid scientists represented in the review and funding process.

Tuesday, February 07, 2006

Grand Rounds vol. 2 no. 20 is up

Grand Rounds 2(20) is up at Science & Politics hosted by everyone's favorite "Red-State Serbian Jewish atheist liberal PhD student," Bora Zivkovic. The cream of the medblogging crop is there for the taking.

While we're at it, here's another quick plug for Bora who was featured by Dr. Nick last week on Medscape.

Monday, February 06, 2006

Political meddling in the scientific process

Thanks to Dr Tara Smith over at Aetiology for the heads-up on Time magazine's recent article on Bush administration meddling in the scientific process. I'm far from being a political blogger, but it's an issue of great concern for all scientists, and not just those in the US.

Missing from the Time article is the outstanding website compiled by Rep Henry Waxman's office on the numerous abuses of scientific inquiry under the current administration.

And, for an eloquent, first-hand example, take a gander at UCSF's Dr Elizabeth Blackburn's sacking from the Presidential Bioethics Commission (if your institutional library doesn't get NEJM, e-mail me and I'll send you my personal copy).

Politics has always driven scientific policy, but usually driven by well-connected scientists and not quite so much in our faces by non-scientist ideologues. Most egregious is the doubletalk: in the wake of the State of the Union address and all the discussion of the need to reduce our addiction to oil, my good friends at the National Renewable Energy Laboratory in Golden, CO, get their budget cut enough to force layoffs of over 10% of the staff. NREL is one of the nation's premier labs for alt energy research, and an arm of the US Dept of Energy.

So much for putting your money where your mouth is.

Wednesday, February 01, 2006

Death by quackery

Just as I was coming up for air after the recent NIH grant deadline, Orac does another tremendous job discussing the case of the 2003 death of a young Coloradan cancer patient at the hands of an alternative "medical" practitioner.

I can't do the story the justice it deserves right now and it's making me sick to even think about the case (septicemia from "UV Blood Irradiation"), so just go to Orac's post. It's no wonder that ScienceBlogs has tapped him as a new team member.

Well, just so you know I'm not lazy but instead exhausted from grant writing, here are a couple of things that I can add:

The "practitioner" billed himself as a naturopathic physician, but even naturopaths won't touch this guy with a 10-foot pole. He did a two-week correspondence course instead of going to one of the four, 4-year North American colleges of naturopathy, then papered his office with diplomas and certificates from institutions that don't even exist.

According to Amber Taufen of Denver's Westword indy weekly, the practitioner has also been implicated in at least another death and a well-documented near-miss. Amber's outstanding article from last summer also cites Colorado naturopaths and CAM advocates as fighting among themselves when it comes to petitioning the state to license naturopaths (only about 13 or 14 states currently have licensing boards for naturopathy):

"Joanie Sevcik-Weichbrodt, president of the Coalition of Natural Health, sees regulation as ineffective. "The problem is, they want only certain schools to be allowed to sit for board exams for licensure," she says. "Only nationally accredited naturopathic schools. They want to put all the other 5,000 to 10,000 natural healers in the State of Colorado out of business; they want a monopoly."

So, "other natural healers" are now using the same argument against naturopaths who favor licensing requirements that CAM practitioners have used for years to rail against MDs.

Blind faith in charlatans who profess to do what allopathic medicine cannot is potentially dangerous and, in this case, even deadly. The continued scientific dumbing-down of the average American and the erosion of critical decision-making skills has created a populace ripe for the picking by unscrupulous marketers and pharmacomedical establishment conspiracy theorists who believe in cures too good to be true. People need to be equally vigilant, informed, and accept personal responsibility in their own conventional medical care as well.

Unfortunately, too many folks spend more time researching their next TV purchase than they do their own healthcare.