Friday, December 30, 2005

Magic and Loss

As you get to know the PharmBoy, you'll learn that music has been a longstanding theme in a life that has been paralleled by scientific training. More on that in future posts, but let it suffice to say that a great many of us can cite theme songs or albums (as we used to call them) that take us back to a place, a person, or an experience.

This holiday week has been a soulful and traumatic time of reflection for me, in between bouts of a sinus infection and chest cold that seems to be circulating the blogosphere. My readings from those who have encouraged me and/or inspired me to start writing brought me back to a place in 1992, when Lou Reed released the album, "Magic and Loss".

Magic and Loss was a concept album devoted to the loss of Reed's two close friends in the course of a year, the mysterious "Rita," and an amazing white blues singer and composer from Brooklyn, Doc Pomus. It is a wistful collection of songs, some of which are oddly the most catchy that Mr. Reed has ever composed. It also accompanied the writing of my first NIH grant, perhaps to prepare me for me own pending loss. I also used some of his lyrics in my CNS pharmacology lectures to our pharmacy students.

But I digress: There are two fabulous pieces of writing this week on Magic and Loss from two of my favorite bloggers:

MAGIC comes from BotanicalGirl on the joyful announcement and circumstances of her engagement to ComputerGuy. The beau sounds like a totally stand-up guy, having taken BG's dad out the night before for beers to ask permission to marry his daughter, a formality that was so much more common in the era of my folks. Great reading, happiness, and promise to end a year that has seen so much public and personal suffering. Love and best wishes to them both.

LOSS comes from Orac Knows at Respectful Insolence. Orac is one of the most erudite and humanistic physician bloggers I have encountered and, as a surgical oncologist, must face death daily in his job. The beauty of his post is the thoughtful and loving discussion of his uncle's illness and a reminder that none of us are immune from this sexually-transmitted, terminal illness we call life.

Orac often draws heated comments from those opposed to his "show-me-the-data" views on alternative medical therapies. For anyone critic who ever doubts the humanity of this physician, visit his link here. A great tribute to his uncle and a reminder that our doctors deal daily with so much more than our own personal frailties.

Tuesday, December 27, 2005

All I wanted for Christmas was...a brand-new liver!

Forbes was among the first I saw covering this rehashed story at the beginning of the month. Yet major press outlets let it lie until the dolldrums of the postholiday news dribbles grew intolerable.

Yes, it is well known that taking too much acetaminophen can damage one's liver to the point of needing a liver transplant. (Acetaminophen is sold in the US as Tylenol, and in various generic forms, but is known also as paracetamol overseas as well as by the abbreviation APAP.)

Normally, say taking 500-1000mg of acetaminophen at a time, twice a day, is totally cool. Your body can handle the small amount of highly toxic metabolite made from acetaminophen in the liver called NAPQI (if you care to read deeper, it is called N-acetyl-p-benzoquinone-imine). Dr Susan Farrell at Harvard did a nice piece on acetaminophen poisoning and Dr Judy Raucy and colleagues, formerly at the University of New Mexico, worked out the enzyme system responsible.

NAPQI is produced from acetaminophen by a liver enzyme called CYP2E1; we normally think of the liver as the place where drugs are inactivated, but many chemicals are made more dangerous when metabolized by the liver. NAPQI is one that is chemically reactive, meaning it'll bind to any major cellular constitutent it comes close to. Fortunately, the liver is home to a lot of glutathione, our major antioxidant defense. And, so, NAPQI is effectively inactivated by glutathione (often abbreviated GSH). So, your liver has the capacity for sopping up NAPQI produced by consuming up to 4 grams of acetaminophen per day. More NAPQI than that and the chemical starts attacking other parts of the liver that are necessary for life.

But there are special cases where it seems folks are taking more acetaminophen than necessary. If you take two Tylenol for a cold (1000 mg), you may also take another dose of NyQuil to get to sleep (1000-2000 mg depending on how you measure). Another dose or two during the day may add another 1000-2000 mg of acetaminophen, and now you are in the range that becomes dangerous for most people. Your liver's ability to sop up NAPQI is limited by its ability to make new glutathione.

A bigger problem is presented by people who are social drinkers, or more than normal consumers of alcohol. Remember that Judy Raucy paper I mentioned above? Well, acetaminophen is predominantly metabolized by CYP2E1. If you have more than 2-3 drinks per day, your 2E1 activity is higher than the average person's. As a result, if you take acetaminophen, you make more NAPQI than the average person who takes the exact same dose of acetaminophen. Add up all the other cold meds, and an active social drinker becomes a candidate for a liver transplant from an over-the-counter drug that has been deemed safe and effective since 1955.

Caught quickly enough (within 24-48 hours), an acetaminophen overdose can be treated with N-acetylcysteine (NAC), a building block that the body uses to make more glutathione. That buys you time but it must be given quickly.

Unfortunately in the US, it is not well known that an herbal agent, milk thistle, also has the capacity to protect against liver damage from acetaminophen. Milk thistle (Silybum marianum) is considered an invasive weed in many parts of the US and grows wild in California in particular. Let me warn you that it is NOT a cure-all and any acetaminophen overdose should be treated in the emergency room. However, many Europeans normally take milk thistle extracts whe taking acetaminophen or any other drug with the potential to be toxic to the liver. Milk thistle is even well-known enough to be recommended before Oktoberfest celebrations.

But in the emergency setting, oral milk thistle will not help you. Milk thistle components are not well-absorbed into the blood, but the liver does concentrate them about 200-fold higher than blood levels. Notably, European manufacturers make an approved, intravenous preparation of milk thistle extract for emergency treatment of poisoning by acetaminophen and the deathcap mushroom, Amanita phalloides. This preparation is not approved for use in the US, but could be used in conjunction with N-acetylcysteine preparations.

The bottom line is that all the recent concern about COX-2 inhibitors has driven consumers away from prescription pain relievers, and even ibuprofen or naproxen. As consumers turn more toward older pain relievers like acetaminophen, they should be wary of the TOTAL amount of acetaminophen being taken in various over-the-counter remedies.

For those with a healthy appetite for alcohol, acetaminophen can be that much more dangerous. Milk thistle, therefore, stands to be one of the more useful of the herbal supplements out on the US market. But even so, some products are better absorbed than others. Readers are recommended to consult objective sites like for more product-specific information since I'm not keen on being linked to one product or another.

Just let it suffice to say that among the crap I see on herbal medicine shelves, milk thistle is one that has very interesting qualities that make it worthy of further study by pharmacologists and physicians.

Something to also consider before going out New Year's Eve!

Monday, December 26, 2005

Rave drug testing - public benefit?

Let me start by saying that the draconian US laws in the 'war against drugs' would ever prevent the following from happening here:

Sounds like a good thing to me: your kid is at a rave party and wants to experiment with some substance that you took blindly 30 years ago without thinking about twice. Fortunately, the party has a booth staffed by a staff of profs and grad students who are willing to anonymously run a sample of your stash through a Bio-Rad HPLC that has a library of comparative chromatograms for over 1000 psychoactive compounds.

Lucky for you, your kid's dope is proper MDMA (methylenedioxymethamphetamine) but his buddy's has paramethoxymethamphetamine (PMA), a compound that induces vomiting and potentially life-threatening hyperthermia. The lab gang notifies the DJ that some bad stuff is circulating, they drop the music a tad, and DJ Funkmaster Phenylethylamine tells folks the appearance of the dosage form (color, size, markings) to look out for.

Such is the case for University of Vienna prof, Ranier Schmid, as reported by John Bohannon of The Scientist. His is part of an amazing drug outreach program to promote safe use of illicit substances to those "who don't consider themselves drug users at all."

In South Australia, a similar group has been stopped from similar on-site analytical chemistry here.

I'll rave (as it were) on these pages about the poor quality control of herbal medicines, yet here is a group of profs and grad students FUNDED to assess your stash in the 15 min it takes to run the Bio-Rad REMEDi HPLC system. Yeah, yeah, my analytical chemistry colleagues will aruge that HPLC is nothing without corresponding MS analysis, but I've got to applaud the Schmid group for attempting to help out on a real-time basis. Not something you'll see on the Bio-Rad website, but certainly a useful public service.

This is also where we face a fight in the US: do we let adolescent/young adults use drugs deemed 'illegal,' or do we help them do so in a safe environment? After all, notification of the contents of a certain dosage form deems it acceptable...right? The right would have you think that any illicit drug use is punishable by the electric chair (or at least a decade in prison); whereas most reasonable folks take a view that if their kids do drugs, they do so in a responsible fashion, certainly more responsible than when they were kids. Are alcohol and tobacco better?

Certainly something to ponder as I drink my wine and puff on my Phillies cigar to commemorate what would be my grandfather's 101st birthday.

Comments welcome...

Tuesday, December 20, 2005

Why Terra Sigillata?

If you Google, “Terra Sigillata,” you’ll get a number of hits for various clay pottery recipes. Very complicated stuff, requiring the use of a deflocculant to separate out large clay particles from the small ones. Terra sig, as it is known among pottery hipsters, is then used to coat finished pieces to produce a very smooth, high luster and waterproof finish.

What does this have to do with pharmacology and natural products?

Terra Sigillata literally means “sealed earth.” In the common potter’s vernacular, “seal” probably relates to the waterproof character of the product. But, in ancient pharmacy history, Terra Sigillata refers to the first trademarked drug product, a small clay tablet or planchet bearing an official mark of authenticity. In this case, the “seal” was a mark for trade and marketing purposes.

Yes, pre-Christian cultures ingested dirt (but only special dirt) as medicine. (Admonishment from my soil scientist colleagues: I meant to say, "soil" - sorry.). Terra Sigillata was a rather fatty clay first harvested around 500 B.C. from a particular hill on the Mediterranean island of Lemnos, now part of Greece. Dug on a special day annually in the presence of governmental and religious dignitaries, the clay was rolled to a defined thickness and pressed with an official seal by priestesses and dried in the sun. Kind of reminds me of my favorite beer, Samichlaus, brewed once a year on Dec 6.

Known as geophagy today, the practice is not as odd as it sounds. Today, we now know that clays contain kaolin (an active antidiarrheal component of Kaopectate), minerals like iron oxides and others like calcium carbonate and magnesium hydroxide that may have served as nutrients or antiacids. Moreover, various ethnomedical cultures have encouraged clay consumption by pregnant women, both to ease nausea and to adsorb dietary alkaloids and steroids present in the plant diet from harming the developing fetus.

Having lived in the southern US for over a quarter of my life, I’m also aware the red clay of the southeastern region is highly regarded for settling the stomach. According to John and Dale Reed in 1001 Things Everyone Should Know About the South,” the practice of geophagy seems to have originated in Africa and was widespread in the 19th century South among the poor of both races. The Reeds claim that the taking of the clay is the source of “sandlappers,” a nickname for South Carolinians. Heck, I’ve even heard Michael Stipe of R.E.M. (and Athens, GA) remark that red clay is in his blood, although I suspect his claim may be more figurative.

I learned of all this great history when I began leafing through a classic 1965 pharmacy history book, “Great Moments in Pharmacy History.” The drug company then known as Parke, Davis & Company, commissioned Robert A Thom, a Birmingham, Michigan artist, to prepare paintings of historical scenes to accompany historical text collected by Prof George A Bender from pharmacy sources worldwide. It’s a great book that can be found through e-tailers focusing on out-of-print texts. If you went to pharmacy school anytime since the mid-1960s, you know what I’m talking about because Thom’s unmistakable portraits can be found in labs and offices in most US colleges of pharmacy.

The idea of Terra Sigillata stuck with me. When thinking of a name for this blog, I didn’t want to restrict it to plants or fungi or soil microorganisms because creatures big and small, terrestrial and oceanic, have been used as sources for medicinal agents. I had certainly known that my predecessors had been culturing soil for novel medicinal-producing organisms since Selman Waksman first discovered streptomycin. But I frankly hadn't realized that the Earth itself had been used as a medicine.

Hence, Terra Sigillata is a metaphor for the fact that the Earth itself has provided medicines to various cultures for centuries.

The trademarking aspect of Terra Sigillata also holds significance for thinking about how important drug branding has become in our current culture, both for the buyer and the seller. Whether declared by a priestess, a charlatan, a shaman, a late-night infomercialist, or a drug regulatory agency, branding carries with it some implicit guarantee of quality or assurance of purity of authenticity.

Or not.

Thursday, December 15, 2005

A Humble PharmBoy Begins to Sow

OK, so I’m a latecomer to blogging.

I was also more than a week late for my own birth.

The blogging spark for me was an Aug 1 2005 article in The Scientist by David Secko. That’s where I first learned of Derek Lowe over at In The Pipeline…and GrrlScientist, Pharyngula, BotanicalGirl, and, YoungFemaleScientist, among others. Secko’s tagline was “Few scientists have caught onto the Internet’s power of posting, commenting, and debating – where are the rest?”

IMHO, pardon the pun, I’ve always been a rather humble scientist. So I first ran “natural products,” “pharmacology,” and “pharmacognosy” through Google Blogsearch and Blogger to be sure that there wasn’t already an authoritative voice on my main research areas. Until there is, I thought I could do a little something to promote my research field and dispel a lot of disinformation out there on naturally-derived therapeutic agents.

What I did find, however, is that this topic is generally represented in the blogosphere by one of two extremes. The study of natural products, or pharmacognosy, represents a branch of the pharmaceutical sciences, taught most often in colleges of pharmacy in a course of mentored didactic and laboratory work leading to a Ph.D. However, natural products are often lumped in, albeit incorrectly, with herbal medicines. Herbal or botanical medicines are considered by many to be “alternative medicine,” that polarizing term used to describe any agent or modality that is not commonly employed in mainstream medical practice.

The polarizing quality of alternative medicine among academic health and life scientists is exemplified by the other extreme in the blogosphere: hucksters using blogs to sell supplements, services, books, etc. with dubious and often irrational claims of cures while feeding the conspiracy theorists with the idea that cures are out there that “they” don’t want you to know.

There are few folks in the middle ground. Orac Knows at Respectful Insolence and Doctor Free-Ride at Adventures in Ethics and Science often take on alternative medical claims in a thoughtful, balanced, respectful manner that is based in fact. But what I see missing in many blog threads, however, is 1) a distinction between the relative validity of each of the alternative modalities and 2) an honest appreciation for what the natural world has lent to modern medicine, healthcare and wellness.

Herbal medicine is arguably the most conceptually accessible area of alternative medicine. A large number of prescription and the over-the-counter (OTC) drugs come from natural sources or are at least chemically-tinkered versions of the drug that occurs in nature. The cholesterol-lowering statins came originally from a fungus, the anticancer drug Taxol/paclitaxel came from the bark of a tree, and various antibiotics came from bacteria and fungi. The oddest case I have come across in my training and reading is that of the topical antibiotic, bacitracin, one of the components of Neosporin. (In fact, all three active components of Neosporin are natural products.) Bacitracin is produced from a bacterium originally cultured in the 1940s from the wound of a girl named Margaret Tracy (hence, the bacterium is called Bacillus subtilis var. Tracy I). I’ll go on about this general topic in subsequent posts.

However, herbal medicine, especially as practiced in the U.S., is a consumer nightmare. Herbal medicines are rarely comprised of a single, well-defined chemical entity. Instead, they can consist of anything from ground-up plant parts to semi-pharmaceutical preparations of plant constituents concentrated many times more than occur naturally. Some of these agents are useless, while others do indeed have the potential for pharmacologic activity, both positive and negative.

The problem is that the U.S. treats this class of drugs as dietary supplements (and, yes, I consider them drugs as defined scientifically; interestingly, the word drug is derived from the French drogue meaning "dried goods" or "dried herbs."). Laws regulating dietary supplements are considerably more relaxed than those that regulate prescription and OTC medicines. Yet, the consumer is often confused since herbal medicines are often sold side-by-side with OTC medicines. I hope to shed light on this confusion.

At the other end of the alternative medicine spectrum are practices like homeopathy. Homeopathic remedies are often made from many of the same plants used as herbal medicines, but they are diluted to the point that no medicinal constituents remain in the remedy. The concept flies in the face of traditional medicines where the principle is, “the greater the dose, the greater the effect.” Homeopaths hold that the greater the dilution of the remedy, the more potent it becomes. Interestingly, the U.S. government does regulate these agents as medicines, due in part to a quirk in legislation introduced by a 1920s N.Y. Senator (Royal Copeland) who was also a homeopath.

These are just two examples of alternative medicine that exemplify the polarization of the field and the difficulties in having a rational dialogue about the topic. Generalizations that “alternative medicine is bad” or that “prescription drugs are nasty chemicals” are not based in scientific fact. I hope to break through these generalizations and discuss alternative medicinal approaches on a case-by-case basis. My plan is to focus primarily on plant-derived medicines, but I will venture into discussions of all alternative therapies where I feel like I have something meaningful to contribute.

Welcome to Terra Sigillata – more on the blog name in the next post.