Google Features Percy Julian, Legendary African-American Chemist
Apr11

Google Features Percy Julian, Legendary African-American Chemist

What a fantastic surprise this morning on the 115th anniversary of Percy Julian’s birth:     I’m beside myself with joy to see this pioneering chemist be recognized by the most prominent search engine in the world. I don’t know where to begin about Julian but I’m sure that many of you have seen The Forgotten Genius, the PBS-produced NOVA life story of the chemist. Julian suffered many indignities in his training, from being denied dormitory residence while earning his B.S. at DePauw University to progression to racial issues limiting him to a M.S. at Harvard. He later completed his Ph.D. work at the University of Vienna in 1931. Julian is probably best known for using natural products as a template for making drugs. His first major feat, the synthesis of physostigmine, a cholinesterase inhibitor from the Calabar bean used to treat glaucoma has been recognized by ACS as a National Historic Chemical Landmark at DePauw University. This 11-step synthesis from phenacetin, the active metabolite of acetaminophen, was completed with his Vienna colleague, Josef Pikl, and students in the laboratory. Julian synthesized cortisone, estrogen, progesterone, and testosterone from the Calabar bean compound, stigmasterol. Later, at Glidden Paint Company, a happy accident led Julian to find that soybean extract (soya oil) also contained the 17-member sterol nucleus, a much more accessible source. At this time, we had absolutely no treatments for rheumatoid arthritis. But cortisone, then made by Merck in a laborious 36-step synthesis, was found in 1949 to transform the treatment of rheumatoid arthritis. However, Merck’s starting material was deoxycholic acid from bovine bile. Julian’s synthetic work beginning with sigmasterol. I could go on. So I strongly suggest that readers consult the ACS National Historic Chemical Landmark dedication and, please, watch The Forgotten Genius. You should buy the DVD, as I did for teaching in my pharmacology classes, but you can watch it in segments at the PBS NOVA...

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Saturday Morning Natural Products PharmChem Radio!
Mar23

Saturday Morning Natural Products PharmChem Radio!

If you’re up on this lovely Saturday morning and looking for something fun and educational to pass the time, dial up wknc.org for the “Mystery Roach” radio show from 8 am until 10 am Eastern time. There, I’ll be discussing the discovery of drugs from nature and the differences between herbal remedies and medicines. The show, hosted by forestry and natural resources doctoral student Damian Maddalena, will be interspersed with psychedelic music from the 60s and 70s. I’ll be monitoring my Twitter account @davidkroll for questions and comments and you can also post at the Mystery Roach Facebook page. Maddalena is an experienced scientist-communicator whose show, named after a Frank Zappa song, celebrated five years last November. The Research Triangle’s independent weekly, INDY Week, recognized Maddalena last year as runner-up for both top radio show and radio host, a tremendous accomplishment for a science and music show in a highly-competitive media market.   Livestream at this wknc.org...

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De-caffeinating pills? Say it ain’t so, Think Geek
May18

De-caffeinating pills? Say it ain’t so, Think Geek

Let me state unequivocally at the outset: I LOVE Think Geek. This purveyor of hip nerdgear – “Stuff for Smart Masses” – has saved me every Christmas, the occasional birthday, and brought me great personal pleasure with their clever offerings. But most important to me about Think Geek is that I know when giving a gift from them, I am giving someone solid science. A mini Van de Graaff generator. A USB plasma ball. And when my office visitors encounter my LED binary clock, I’m asked, “What the heck is that?” My next two purchases are likely to be the Pet’s Eye View Digital Camera for the PharmBeagle and the DIY Guitar Pick Punch for me (even though you could buy 80 top-quality guitar picks for the same price). But I will not be buying Rutaesomn® Sleep Aid – De-caffeinating Chill Pills. The product is billed as being a pill that speeds metabolism of caffeine from your day-long coffee and energy drink binges. Take it 2-4 hours before you want to go to sleep, “helps get rid of caffeine in your body keeping you awake.” Well, what is it exactly? Rutaesomn® is an herbal extract from Evodia rutaecarpa that is also known in Chinese traditional medicine as Wu Zhu Yu where it’s used for alleged weight-loss activity. The biologically-active chemical in the herb is called rutaecarpine. So, what does this have to do with caffeine? Well, rutacarpine influences the activity of our major caffeine-metabolizing enzyme called CYP1A2. This is one of a family of over 50 such enzymes that allow us to handle drugs and chemicals we’ve encountered throughout our evolution, including even chemicals that haven’t yet been made. These CYPs, or cytochrome P450 enzymes, could be thought of as the catalytic converters of the body. You’ll find them mostly in the liver and kidney but almost every cell of your body has some small amount. Most of the time they change chemicals into their less active forms (though there are important exceptions where they make drugs more active or even carcinogenic). Usually, the CYP clips off or modifies a part of the chemical to make it more water-soluble and, therefore, more easily excreted in the urine. This is how CYP1A2 works to metabolize and inactivate the stimulant activity of caffeine. But if you do a little reading, you’ll learn that rutaecarpine is an inhibitor of CYP1A2. Wait a minute. Doesn’t that mean that rutaecarpine would increase the length of caffeine action in the body? Wouldn’t taking rutacarpine keep you awake longer after a caffeine binge? Well, yes, if it’s taken in a high enough dose. But here’s what...

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Bad news for Bionovo and herbal drug development
Mar11

Bad news for Bionovo and herbal drug development

A pharmacognosy colleague contacted me on Friday morning with word that the botanical drug development company Bionovo was closing its chemistry group. Well, the news is actually worse as judging from this 8 pm Friday press release: Bionovo, Inc. (OTC Link Platform: BNVI.PK) today announced that it will need to obtain substantial additional funding to achieve its objectives of internally developing drugs. The Company reduced its workforce by over 90%. The remaining management of the Company will receive reduced cash compensation until either adequate financing can be obtained or the Company is sold.  The Company can not make any assurances about either of these events.  As previously announced, management and the board of directors are continuing to explore strategic options for the Company.  Management is currently reviewing the status of the ongoing clinical trial for Menerba. The Company does not currently have adequate internal liquidity to meet its cash needs.  If sufficient additional funds are not received in the near term, the Company may not be able to execute its business plan and may need to further curtail or cease operations. Bionovo has been the rare superb example of a company that’s been trying to develop FDA-approvable drugs based on Chinese traditional medicine. Led by Isaac Cohen, a UCSF guest scientist and Doctoral of Oriental Medicine, and chief medical officer, Mary Tagliaferri, Bionovo took a hard, science-based approach to identifying herbal extracts for cancer and women’s health issues. Cohen and colleagues at UCSF and elsewhere examined Chinese herbal medicines for their biochemical and cellular effects based upon their traditional use. Some of their early work was with a molecular endocrinology physician-scientist Dale Leitman, then at UCSF. Leitman has a solid track record in the transcriptional regulation of estrogen receptor-beta (ERβ), particularly by natural products such as soy isoflavones. Leitman led the group that reported in 2007 that a 22-herb extract, Bionovo’s MF101 (Menerba), had selective ERβ agonist activity with the potential for treating menopausal symptoms without increased risk of breast cancer. This extract advanced to Phase III trials last October. Even more interesting to me was Bionovo’s extract of Scutellaria barbata (BZL101, Bezielle). Given the recent enthusiasm in searching for drugs that targeted the aerobic glycolysis phenotype of many cancers, BZL101 was exciting because it had these effects in cell culture and was formulated into an oral preparation with good bioavailability. (I should make the disclaimer here that my wife, a former Duke University breast oncologist, enrolled patients in a Phase I trial of BZL101 and was co-author of a 2008 ASCO abstract on the results. However, she received no personal compensation for this work and we have never...

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Undeclared drugs in herbal and non-botanical dietary supplements

This post appeared originally on 13 April 2009 at the ScienceBlogs home of Terra Sigillata. An interesting question arose the other day when we discussed the Key West acupuncturist who was diverting prescription drugs for personal use as well as in her practice. While we are not certain that the defendant put the cited muscle relaxants and anxiolytics in remedies doled out at her practice, we doubt that the demographic she targeted would be too impressed if she were to hand out prescription drugs. This scenario led our scientific and blogging colleague, DrugMonkey, to ask how common it might be for alternative practitioners to dope their herbs with prescription drugs exhibiting known efficacy. He also notes how disingenuous this practice might be in that the alternative practitioner is admitting in doing so that their herbs and elixirs have no efficacy on their own. I can’t speak to trends among individual practitioners but this practice takes a page from the big boys: the dietary supplement industry. Adulterating commercial herbal products with prescription drugs is so common that the US FDA is keeping a running tally of actions against companies selling supplements containing “undeclared drugs”: the polite regulatory term for deceptive doping of a useless product with a real drug. We’ve spoken about these cases several times before [1, 2, 3, 4, 5, 6]. Most common approaches have been to dope weight-loss supplements with sibutramine, a prescription amphetamine-like, serotonin/norepinephrine reuptake inhibitor sold in the US and Canada as Meridia®. The US FDA list on this class of deception has increased from 28 to 69 products since 22 Dec 2008. For example, we get a large number of hits from readers searching for apple cider vinegar capsules and whether they can help one lose weight – well, yes they can, if they contain sibutramine, of course. Another common adulteration tactic is for erectile dysfunction supplement manufacturers to boost their products with prescription phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil (Viagra®) or related compounds. So popular is this approach that the same manufacturer cited above for sibutramine-adulteration of apple cider vinegar products has also been found guilty of adding PDE5 inhibitors to their “Long Weekend” product. At least their business model is consistent, eh? A recent FDA investigation of such supplements sold online revealed that up to one-third of products are so adulterated. This may all seem like fun and games but there is at least one case in the literature where supplement doping has been associated with unusual cases of prostate cancer (Clin Cancer Res 2008:607-11). In this case, the bodybuilding supplement Teston-6 was found to contain testosterone and other compounds...

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