Category → Ripped From the Pages
Genetic Tests And Rimonabant: Coulda, Woulda, Shoulda
Here’s something I missed while finishing up that blood thinner cover story. Last week Reuters reported that genetic testing might have helped save rimonabant, the ill-fated obesity medication once touted as a future blockbuster. Rimonabant, which blocks the cannabinoid-1 receptor, the target of marijuana’s psychoactive ingredient, appeared to help people lose weight. But it also increased the risk of psychiatric side effects, as we wrote back in 2009. The drug never won US approval and was pulled from the market in Europe in 2008.
Reuters’ story was based on this report from The Lancet. The report (and accompanying press release) decribe CRESCENDO, a large clinical trial of rimonabant which was halted midway through because regulatory authorities were concerned about suicides in people taking the drug.
The story actually focused on a small part of the Lancet paper’s discussion section, where Topol describes the lessons drugmakers should take away from the CRESCENDO trial.
Endocannabinoid blockade could have proven viable, if a genome-wide association study had been done to establish what sequence variants are linked with suicides, suicide attempts, or significant neuropsychiatric side-effects.
And here’s what Topol told Reuters about genetic testing.
“Finding the gene for severe adverse drug reactions is a lot easier than we ever thought it would be,” Topol said in a telephone interview.
Topol thinks if they had thought to collect genetic information on the study’s more than 18,000 participants, they might have spared the drug.
“We probably could have figured out genomically who was susceptible and that drug could be quite viable,” Topol said in a telephone interview.
I guess a genome-wide association study might have been interesting. It’s a shame one doesn’t seem to have been conducted. Still, I’m not sure it would have been guaranteed to determine which patients were more susceptible to suicide. These types of studies have limitations, which this article from JAMA describes best:
GWA studies are an important advance in discovering genetic variants influencing disease but also have important limitations, including their potential for false-positive and false-negative results and for biases related to selection of study participants and genotyping errors.
Image:C&EN
On Blood Thinners And Rat Poison
C&EN’s cover story this week is about finding replacements for the blood thinner warfarin, something that hasn’t happened in the more than fifty years since the drug went on the market.
Warfarin prevents blood clots from forming and reduces active clots as well. When it works, it’s great for preventing strokes. As a bonus, it’s a dirt cheap pill, costing on the order of a couple of cents a day. But the trouble is that warfarin doesn’t always work well. It is extremely unpredictable in the body. Foods and other drugs affect its activity, as do certain genetic traits.
The last thing you want to do is to take too much or too little warfarin. Too much warfarin could lead to uncontrolled bleeding, something that can be deadly in a place like the brain. And of course too little warfarin won’t be effective at preventing clots. So patients on warfarin must constantly monitor how well their blood is clotting, so their doctor can get their dose just right.
The fact that it’s easy to overdose on warfarin is a pain for doctors and patients. But it comes in pretty handy in warfarin’s other, perhaps less well-known application: rat poison. It seems that messing with rodents’ blood clotting pathways is a very efficient way to off them. My cursory research indicates that we’ve got many rodenticide options, and warfarin isn’t the most common one. I couldn’t find warfarin at three different D.C. hardware stores. But it’s still available online.
YOUR KEYWORD FOR THIS BLOG IS: COMING
As an aside: medical websites seem to use the name “coumadin”, but the rat poison boxes read “warfarin”. I’d love to know the history behind this name divergence. It could be another instance of name-changing to assuage patient fears. I can certainly understand how a patient would find it disconcerting to see a giant box of their blood thinner in the pest control aisle at Home Depot. Think of how a nuclear magnetic resonance spectrometer uses essentially the same technology as a magnetic resonance imaging instrument. But the name you see used in the health field drops the “nuclear”.
Scientists On The Move
I like taking the time to read the fine print in journal articles. When I first read the antibiotic work I posted about yesterday, I noticed that a few of the authors on the paper had little crosses next to their names. If you go to said fine print, you will find that they are no longer at GSK, but are located elsewhere. I’m no Chemjobber or Electron Pusher, but I try to pay attention to researchers’ moves.
Drake S. Eggleston, Fabrice Gorrec, Earl W. May & Alexandre Wohlkonig
Present addresses: Innovalyst, 1000 Centre Green Way, Suite 200, Cary, North Carolina 27513, USA (D.S.E.); MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK (F.G.); OSI Pharmaceuticals, 1 Bioscience Park Drive, Farmingdale, New York 11735, USA (E.W.M.); Vrije Universiteit Brussel, VIB Department of Molecular and Cellular Interactions, Pleinlaan 2, 1050 Brussels, Belgium (A.W.).
Platensimycin On My Mind
Yesterday we posted a Latest News item that heralds a potential new class of antibiotics. This is a topic near and dear to my heart, because I worked on the total synthesis of a potential new antibiotic in graduate school. Of course, my time in grad school also taught me not to trumpet ‘potential new antibiotics’ as the next big wonder drugs, because the molecules in question almost always have yet to be tested in people, a process that seldom goes perfectly smoothly.
There was a slightly different twist to this story that made me think it deserved attention: it seems to be nudging researchers and saying, “Don’t get so caught up in the hoopla of fancy genomics technology that you ignore old antibiotic targets that still need exploring.”
In the study, researchers at GlaxoSmithKline, in collaboration with the Wellcome Trust’s Seeding Drug Discovery Initiative and the U.S. Defense Threat Reduction Agency, found a small molecule that blocks DNA gyrase, or type IIA topoisomerase, in an entirely new way. The molecule was effective against a panel of drug resistant bacteria and revealed new nuances of the gyrase mechanism to boot.
Since the news story discussed revisiting old antibiotic targets, I thought I’d spend some time reminding Haystack readers of a search for a new one. Over the last few years, C&EN has extensively covered the story of platensimycin, a promising antibacterial with an exciting target, first isolated from a South African soil sample.
Here’s an abbreviated platensimycin timeline:
May 2006: Merck researchers report the structure of platensimycin and describe its intriguing activity- it blocks FabF, an enzyme involved in fatty acid synthesis, one that has never before been targeted by antibiotics used in the clinic.
October 2006: K.C. Nicolaou group at Scripps Research Institute reports the first total synthesis of racemic platensimycin, setting the stage for making analogs for exploring its bioactivity.
April 2008: Lisa Jarvis’s C&EN cover story counts platensimycin among the natural product antibiotics in development.
March 2009: Microbiologists report that pathogens can scavenge lipids from their mammalian hosts, suggesting that platensimycin’s target (part of the lipid synthesis pathway) may not be a viable target for an antibiotic, after all.
August 2010: I contacted Merck to ask about the current status of platensimycin. Here is what Dr. Sheo Singh, Merck Research Labs Director of Medicinal Chemistry, who led the discovery team on platensimycin in 2006, had to say: “As part of the merger integration of Merck and Schering-Plough, platensimycin is being evaluated and prioritized along with all the other compounds in the early stage pipeline.”
Your Molecular Essentials
Well, the ‘molecules you’d take to a deserted isle’ results are in. A special thank you to Dr. David Kroll (aka Abel Pharmboy) over at Terra Sigillata for sharing his own thoughts on the topic and encouraging more folks to take part in the survey. You were all over the map, picking 29 different molecules in all. Just one of you shared the philosophy of the original paper’s authors, picking molecules that have intriguing chemical structures and chemical stories. Most of you went the practical route- assembling a molecular first-aid kit for any ailments that might happen to come your way, as Dr. Kroll had in his post. And a few of you went in a more, shall we say, recreational direction.
In the ‘beautiful molecules’ category, you picked palau’amine and vinigrol.
You have protection from the sun and the bugs (avobenzone, the insecticide imidacloprid), antibiotics (amoxicillin, streptomycin, Cipro), allergy meds (diphenhydramine aka Benadryl and pseudoephedrine aka Sudafed), and painkillers of all stripes, from morphine to ibuprofen. A few people prepared for bouts of indigestion (loperamide aka Immodium) and epilepsy (the anticonvulsant lamotrigine). And one person may expect to find a friend on the island, since they packed the contraceptive norgestimate.
You also packed quinine, which could easily fit into the awe-inspiring structure category as well as the medicinal category, for its fever-reducing and antimalarial activity.
A few recreational molecules made the list, like LSD, THC, and cocaine. But I give props for creativity to the person who selected just one molecule, albeit a very large one: The DNA of Emma Watson.
Curious what the ‘winning’ molecule was? It was a tie between good old penicillin and aspirin, with ethanol, caffeine, and water close behind.
Image:C&EN
Freeing The Newt Within
Who hasn’t dreamed of having extraordinary powers? Telekinesis, flight, or, perhaps, a third arm?
In the upcoming 2 August issue of C&EN, Sophie Rovner has a story on limb regeneration and its promise for human therapy. Newts are champions at regrowing lost arms and legs, she told me. Which got us to talking about whether we’d like to grow some extra limbs, as a tadpole has in one of the story’s images.
My extra limb would be very useful as a cup holder for my favorite beverages while I’m working on destroying cities’ downtown areas.
A third arm offers many potential benefits—skiers could use an extra pole, helping better control their movement and speed; rock climbers could be like Spider-Man, able to dangle from a sheer cliff ledge and eat lunch at the same time; and gymnasts would be able to do handstands with unnatural ease. I, however, would use that third limb to hold my coffee bowl (I would say mug, but it’s way too big to be called that) like a champ while I type, edit for C&EN, walk, photograph, sleep … It might seem a waste, but using my third arm for holding coffee is more rewarding to me than using it for nefarious purposes like Doc Ock does. Although without my coffee, Washington, D.C., had better watch out!
But having a third upper extremity would tax a person’s body more than superhuman characters make it appear on the big screen. To maintain equal strength, let alone build more, you’d have to spend longer at the gym (or dangling from a wall) because you’d be working more limbs. But in today’s time-crunched, highly caffeinated society, more time to work out (any time to work out) is hard to come by. And the extra deodorant and special clothes needed would greatly increase cost-of-living expenses, not to mention the massages to work out muscle tension caused by the weight and use of the arm on a body not designed for an extra limb. That would make it a pretty expensive cup holder.
So, I’m not exactly convinced that the extra appendage is really all that desirable. I’m open to debate, however. What extra body part would you want (keep it clean—we’re a family blog!), what would you do with it, and how (or how not) would it alter your day-to-day?
Doc Ock photo graciously provided by wagner_arts, coffee by Shutterstock, and Photoshopping work by Robin Braverman of C&EN.
Positive Results for Onyx’s Myeloma Drug Carfilzomib
This morning Onyx Pharmaceuticals shared good news about its multiple myeloma drug candidate carfilzomib- the compound helped 24% of the multiple myeloma patients enrolled in a Phase 2b clinical trial, all of whom have seen other therapies fail. Onyx’s stock was up over 21% on the news, last we checked. The company is hammering out the details of filing a new drug application (NDA) for carfilzomib, something they intend to do by the end of 2010.
Multiple myeloma is a type of blood cell cancer that’s very challenging to treat, with relapses a fact of life. Patients in Onyx’s trial “can expect to respond to therapy only 11 percent of the time and survive for only six to 10 months,” Michael G. Kauffman, M.D., Ph.D., Chief Medical Officer of Onyx Pharmaceuticals, said in a press release. In these patients, when carfilzomib worked, the duration of the response was over seven months.
Carfilzomib is part of a new generation of myeloma drugs that are just starting to emerge, as we wrote about in C&EN last year. Continue reading →
What Molecules Would You Take To A Remote Isle?
In this week’s Newscripts I interviewed the authors of an entertaining article that ran in last month’s Chemistry & Biology, about the five molecules the authors would take to a deserted island. Rather than falling back on the obvious choices, Thomas U. Mayer and Andreas Marx of Germany’s University of Konstanz picked compounds with a cool chemical backstory. Their choices were:
- FK506
- cidofovir
- colchicine
- Quimi-Hib
- Gleevec
So now we put it to you- what’d the authors get right? What’d they miss? We’ve created a survey so you can weigh in.Click here to take survey. We’ll post the most interesting results in a week or so. Or just use the comments section.
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