“Pick A Powder” RIP?
Apr27

“Pick A Powder” RIP?

I wrote this post on April 15th for my monthly gig at the Science-Based Medicine blog but just thought of it again this weekend as I drove past the BC Powder historic building in downtown Durham, NC. One thing I've observed since bringing Terra Sig to CENtral Science last summer is that we get a readership that is distinctly different than what I have seen when blogging in more biomedical environs (at least as far as institutional IP address hits tell me on SiteMeter.) So, I wanted to update this post for you - Dear C&EN/CENtral Science reader - and add a few pictures. Truth be told, I really like this post in part because I love the pharmacy history of the American South. I also think that we could do a better job down here of using NASCAR enthusiasm to promote careers in science, technology, engineering, and mathematics (STEM). The following is adapted from a post that appeared originally on 15 April 2011 at Science-Based Medicine. After spending the first 21 years of life in New Jersey and Philadelphia, I ventured to the University of Florida for graduate school. For those who don't know, UF is in the north-central Florida city of Gainesville - culturally much more like idyllic south Georgia than flashy south Florida. It was in Gainesville - "Hogtown" to some - that I first encountered the analgesic powder. I believe it was BC Powder, first manufactured just over 100 years ago within a stone's throw of the Durham, NC, baseball park made famous by the movie, Bull Durham. I remember sitting with my grad school buddy from Kansas City watching this TV commercial with hardy men possessing strong Southern accents enthusiastically espousing the benefits of BC. I looked at Roger - a registered pharmacist - and asked, "what in the hell is an analgesic powder?" What I learned is that powders of analgesic compounds were one of the individual trademark products of Southern pharmacies during the early 1900s. Here's the simple reason from an NCPedia reprint of a Suzanne Mewborn article entitled, Inventive Spirit: Pain Relief, in the Fall 2006 issue of Tar Heel Junior Historian: It was very common for druggists in the early 1900s to buy raw materials and make their own prescriptions. Pills were harder for the local druggist to make, so pain-relief powders developed as a regional heritage. Many of these powders became quite popular with mill and textile workers needing to calm headaches induced by long hot days with loud machinery. The original powders contained a precursor to acetaminophen called phenacetin (also shown in the old photo as acetophenetidin - good...

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GSK to sell iconic Elion-Hitchings building
Apr18

GSK to sell iconic Elion-Hitchings building

On the heels of last week's announcement that GlaxoSmithKline was selling off 19 consumer products comes news today by Laura Oleniacz from the Durham Herald-Sun that the drugmaker is liquidating some of its facilities on its Research Triangle Park campus. One of these buildings is the futuristic structure built in 1972 for then Burroughs-Wellcome as designed by famed architect, Paul Rudolph. Now known as the Elion-Hitchings building in honor of the Nobel prize-winning chemists, the facility is one of the most recognizable landmarks in pharmaceutical history. Click here for a fantastic series of copywritten photos from architect Kelvin Dickinson of The Paul Rudolph Foundation. You may recognize the building from the movie, Brainstorm, with Christopher Walken and the late Natalie Wood. (Her final film, the movie was released almost two years after her Wood's death.) Elion and Hitchings were awarded the 1988 Nobel Prize in Physiology or Medicine, not Chemistry, for their synthesis of antimetabolite drugs - analogs of nucleic acid bases that selectively killed tumor cells but became treatments for gout (allopurinol), herpesviruses (acyclovir), and HIV/AIDS (AZT; zidovudine). Of interest to ACS readers and others interested in pharmaceutical history, the Elion-Hitchings Building is located almost directly across the Durham Freeway (NC-147) from the ACS National Historic Chemical Landmark at Research Triangle Institute, now RTI International. That landmark honors the discoveries of Taxol and camptothecin by the late Monroe Wall and still-spry Mansukh Wani. One might ask why the Elion-Hitchings Building was never nominated for an ACS landmark. My guess is that many of the antimetabolite compounds synthesized by Elion and Hitchings were made before Burroughs-Wellcome's US facilities moved from New York to North Carolina's Research Triangle Park in 1970. After Hitchings retired in 1967, Elion stayed on almost until her death in 1999, still working with young researchers both at BW and at nearby Duke University. Of note, Elion's group did synthesize acyclovir at the RTP facility. I love old buildings, even if old in this case is the early 1970s. So, what could be done with this building? I have an idea: hipster scientist condominiums. Research Triangle Park was officially chartered in 1959 long before the idea of mixed-use developments - gasoline was only about 16 cents per gallon and the whole idea of recruiting companies from the North to North Carolina was that workers could have inexpensive housing with lots of land out in the surrounding rural areas. As a result, the immediate RTP area is known for its relative lack of housing and services such as restaurants, coffeeshops, and brewpubs (i.e., places that scientists could gather for creative discussion). Most companies have their own services,...

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The Man Who Gave Us Epo
Dec20

The Man Who Gave Us Epo

I learned over the weekend via this tweet from Serena Stockwell at Oncology Times that Eugene Goldwasser passed away on Friday at age 88. The biochemist and renal physiologist who spent most of his career at the Argonne National Cancer Hospital and Department of Biochemistry and Molecular Biology at the University of Chicago (web page) demonstrated that a hormone made in the kidney could increase the number of new red blood cells, a major advance in physiology. His laboratory purified the protein hormone, erythropoietin (or Epo), from sheep in 1971 and from humans in 1977. While a remarkable discovery of its own, Goldwasser's partnership with then-Applied Molecular Genetics (Amgen today) led to the first- and second-generation recombinant biopharmaceuticals, erythropoietin and darbopoietin, and other versions such the the PEGylated EPO, Mircera. These drugs have transformed the lives of kidney dialysis and cancer patients, raised a furor in competitive sports - cycling in particular - and have been central to some of the most robust legal wrangling and medical costs discussions of our generation. Serena pointed me toward this obituary by Merrill Goozner, who devoted an entire chapter to Goldwasser in his 2004 book, The $800 Million Pill - sounds as though I have another book to go on my Christmas list. Goozner noted that Goldwasser, a Brooklyn native, attended the University of Chicago in the biological sciences and worked during World War II on scientific approaches against chemical warfare agents. I could find only one publication on Goldwasser's work in this regard - not a surprise as much of the work is likely to have been classified. This 1947 paper appeared in the Journal of Pharmacology and Experimental Therapeutics (1947; 89:1-13) describing work in 1942 and 1943 on the use of 2,3-dimercaptopropanol (dimercaprol) against the vesicant (blistering) war agent, Lewisite - chlorovinyldichloroarsine or 2-choloroethenyldichloroarsine (an arsenic compound having nothing to do with this month's arsenic adventures.). Goozner notes that Goldwasser completed his doctoral work at Chicago after the war and worked at the Argonne Cancer Research Hospital, a US Atomic Energy Commission-supported institution on the University of Chicago campus. This 1953 NEJM editorial notes that the hospital was headed originally by Leon O. Jacobson, a physician who together with Goodman and Gilman at Yale popularized the use of one of the first synthetic chemotherapy drugs, nitrogen mustard, a therapeutic derivative of chemical warfare agents that exhibited efficacy against leukemias and lymphomas. (As an aside, Goldwasser wrote a beautiful history (PDF) of his mentor and collaborator, "Jake," for the National Academies Press after Jacobson's death in 1992.). Goldwasser began investigating the regulation of the blood-forming elements and demonstrated in this 1956 Nature...

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Apixaban trial halted, eight others continue
Nov19

Apixaban trial halted, eight others continue

After writing this week about the new, direct-acting antithrombotic drugs that threaten to replace the stalwart anticoagulant, warfarin, comes news that the joint BMS/Pfizer development of apixaban has hit a snag. From Jonathan Rockoff and Kathy Shwiff in the Wall Street Journal: Pfizer Inc. and Bristol-Myers Squibb Co. said they've halted one the key trials for an experimental blood-thinning drug that is one of their brightest pipeline prospects, though other pivotal studies remain on course. The phase III study of apixaban was examining whether the pill reduces the incidence of strokes or heart attacks caused by coronary heart disease, but early results indicated it didn't while raising the risk of bleeding. The companies said they had acted at the recommendation of an independent data-monitoring committee. All patients will be taken off the drug and the results evaluated and made public, the companies added. Eight other trials of apixaban are ongoing in other patient populations. Mechanistically, apixaban is most similar to rivaroxaban (Xarelto, Bayer/J&J) a direct Factor Xa inhibitor discussed this week at the American Heart Association meeting. Rivaroxaban exhibited efficacy similar to warfarin in reducing clots of atrial fibrillation patients but had caused fewer spontaneous bleeding episodes. A careful examination of the opposite effect of apixaban in patients with coronary heart disease will be essential to understanding whether this is a function of the drug (relative to rivaroxaban) or peculiar to the patient populations...

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Blood Clotting and Benzamidine
Nov16

Blood Clotting and Benzamidine

Now that I don't have to be graded on my memorization of the blood clotting cascade, let me just step back for a second and express awe for the physiological process of hemostasis. Think about this: we have to maintain our blood in a freely circulating form 99.999% of the time but as soon as there is a breach in the system, we have to quickly mobilize a cascade of events to prevent catastrophic blood loss. Pharmacological fiddling with this exquisitely controlled process is bound to have complications. But we have learn to walk this tightrope with drugs to prevent blood clots following stroke, orthopedic surgery, vascular stent implant, and other procedures and disorders that might cause such emboli to travel to our lungs, heart, or brain. News yesterday from the American Heart Association meeting in Chicago brought our attention to a new class of anticoagulant drugs that may finally knock the coumarin, warfarin (Coumadin, racemic mixture), off its lofty pedestal as the oral antithrombotic drug of the last six-plus decades. Yes, the standard of care for about 65 years. The large, ROCKET AF trial presented yesterday had investigated the efficacy and side effect profile of warfarin relative to rivaroxaban (Xarelto, Bayer/J&J), a once-daily, oral inhibitor of the clotting factor, Factor Xa (part of a complex that converts prothrombin to the endogenous coagulation protein, thrombin). To understand why this new drug is noteworthy, we have to consider how warfarin works. Warfarin acts upstream of Factor Xa by inhibiting Vitamin K epoxide reductase (VKOR), a crucial enzyme in the activating gamma-carboxylation of several clotting factors, not just Factor Xa. Vitamin K is the name for a group of 2-methyl-1,4-naphthoquinones that transition through a hydroquinone and epoxide in this reaction cycle. The primary disadvantages of warfarin are the need for frequent monitoring of bleeding time (or INR, international normalized ratio), the interaction with foods containing vitamin K, and the risk of bleeding (particularly intracranial bleeding). Beyond the food-drug interaction, mostly with green leafy vegetables, polymorphisms exist both in the VKOR target and CYP2C9, the primary enzyme responsible for metabolizing warfarin. Rivaroxaban, an oxazolidinone, and the recently-approved dabigatran (Pradaxa, Boehringer-Ingelheim), a benzamidine, bypass many of these problems via their own distinct mechanisms. Xarelto/rivaroxaban directly targets the serine protease activity of Factor Xa. Pradaxa/dabigatran is a direct thrombin inhibitor targeting the serine protease activity of this downstream coagulation factor. The Thomson Reuters article yesterday by Ransdell Pierson and Debra Sherman on the 14,000+ patient ROCKET AF trial noted that both Xarelto and Pradaxa have now been shown to be roughly equivalent to warfarin in efficacy, albeit in different patient populations, but much better with...

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Quintiles’ Dennis Gillings Profiled in Forbes
Nov05

Quintiles’ Dennis Gillings Profiled in Forbes

There's been lots of discussion in the blogosphere and Twittersphere this week about Matthew Herper's excellent profile of CRO CEO, Dennis Gillings, entitled Money, Math, and Medicine, and a follow-up this morning on Gillings' comments about China overtaking the US in biotech prominence. The profile is planned for the November 22nd print issue of Forbes magazine but appeared online earlier this week. Gillings is a local hero in the Research Triangle area as a former UNC-Chapel Hill professor who has developed a privately-held company that Herper says has "annual sales of $3 billion, $500 million in earnings before interest, taxes, depreciation and amortization, and $400 million in free cash flow." Gillings and his wife, Joan, also gave a $50 million gift to UNC in 2007 - the largest ever in the 221-year history of the university - and are the namesakes of their highly-regarded Global School of Public Health (disclosure: my wife is a MPH student and preventive medicine resident there). The buzz about Herper's profile article is due partly because of how Quintiles and other CROs are viewed in academic medicine units that try to compete with these companies for pharma-sponsored clinical trials. Some critics, such as Robert Harrington of Duke's Clinical Research Institute (DCRI), state that CROs lack appropriate distance from their corporate clients. For a basic scientist, I've been thinking a fair bit about clinical trials ethics after I attended a talk last week by Ross McKinney, MD, head of Duke's Trent Center for Humanities, Bioethics, and History of Medicine (I wrote about my impressions here for my monthly gig for the cooperative blog, Science-Based Medicine). What struck me instead from Herper's article is a revenue-sharing model set up in 2000 by Gillings, one that was first viewed by analysts as ill-advised but that turned out to be quite prescient. Again, from Herper: Gillings' solution is to help his clients by investing cash they can use to develop their medicines, in return for royalties if the drug makes it to market. . . . . .Quintiles invested $110 million in [Eli Lilly's antidepressant Cymbalta] and spent $300 million marketing it. It has fielded a third of the sales reps pitching the drug to internists. In return it got an 8.5% royalty on Cymbalta's U.S. sales (now $2.6 billion a year) for the first five years the drug was on the market; it gets a 3% sales royalty through 2012. It's not clear to me whether Quintiles invests in drugs who trials they manage but regardless, this approach seems to represent a significant conflict of interest. Gillings emphasized to Herper that the company takes "a paranoid approach"...

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