Archive for category Better Living through Chemistry

Blue Healer: Ellie’s rough road

So lately I’ve been helping to take care of a dog that has proven to be a remarkable, and damned near heartbreaking, challenge. (Well, considering we all live indoors and have plumbing and electricity and stuff. I don’t want to get too high-flown here. A Jack London story this ain’t.)

Ellie is a 12- or 13-year-old Australian Cattle Dog mix, weighing in at about 60 pounds. (An alternative name for this breed is “Blue heeler.”) I first became acquainted with her toward the end of last year. A friend of mine does a lot of house-sitting and pet-sitting, and I often lurk nearby when she does; Ellie’s family is a frequent client. My initial meetings with Ellie were on the turf of her owner Jil’s parents, who live less than a mile from Jil and her husband and own a similarly aged, better sighted, more arthritic pooch named Mollie. Mollie’s owners are also frequent clients of my friend the sitter. When Jil is out of town, Ellie usually stays at Mollie’s, and when Jil and her parents are both out of town (which happens more often that you might think, not that I’m reading your mind), the dogs and my friend all stay at Mollie’s. Which is a hell of a nice house, since you asked.

With that burst of irrelevant details out of the way, I’ll describe the problem and the (apparent) (re)solution. Read the rest of this entry »

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Incivek? Sounds like an alien from “Dr. Who.”

I will never fathom how marketing comes up with brand names for Rx drugs. Anyway, the FDA officially approved telaprevir (see post below) on Monday, May 23.

From Zennie62’s blog on SFGates (San Francisco Chronicle), here’s an interview with Steve Goodwin, a chief engineer who was diagnosed with hepatitis C, who was treated with telaprevir/Incivek. In the video, Goodwin tells “how he came to find out about Incivek via the use of the website Clinical Trials, at clinicaltrials.gov, and how it’s helped him to a more normal path of life.”

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“My baby” is about to graduate! FDA panel recommends Vertex Pharma’s telaprevir for approval to treat hepatitis C

This week, panels of non-FDA experts reviewed the clinical data for Merck’s* boceprevir and Vertex’s telaprevir for potential market approval as first-in-class** treatments for patients infected with hepatitis C.

Panel to FDA: Give OK to Vertex hepatitis C drug

Are telaprevir and boceprevir perfect drugs? No. Each has side effects. There are the proven side effects of Xarelto even. I’ll note, however, that the “nasty rash,” the most common adverse effect (AE) of telaprevir, was generally mild to moderate and treatable with antihistamines or corticosteroid creams. Only 2% of subjects discontinued treatment because of the rash. So it’s an AE that is tolerable.

The drugs will also be quite expensive: $35-40K per course of treatment. Yikes almighty! Yet these are complex molecules that are not facile to synthesize. Also, consider that a liver transplant costs in the order of $250K to $310K (and higher).

VX-950 a.k.a. Telaprevir

That’s the structure of “my baby” above. Of course, it’s not strictly mine. Not by a long shot, but with all the work I did on that molecule, I feel like one of its many parents. We had a hell of a team at Vertex, and there’s a critical piece of the molecule that was added by Mark T., a wicked smart medicinal chemist, who was then at Lilly (former collaborators; Lilly and Vertex had, uh, differences in approach and thus had a fairly amicable divorce). My contribution was to study the detailed inhibition kinetics of VX-950, using isolated HCV protease for in vitro assays. I demonstrated that VX-950 was a slow binding inhibitor with a slow off-rate. It’s sticky in other words, and hangs onto the the protease for a good while before being hydrolyzed off the enzyme by water in the cell.

The close teamwork of biochemists/enzymologists and virologists at Vertex proved to be a very powerful combination. The virology team was able to demonstrate the efficacy of the protease inhibition in their viral RNA replication assay, and that the slow off-rate appears to play a role. These experiments were performed in 2003/2004, and became pivotal elements of the package, which included major contributions from medicinal chemistry, protein chemistry, process chemistry, toxicology, and pharmacokinetics, which brought VX-950 (telaprevir) forward as a clinical candidate. And now…well, I wonder what its brand name will be?

The odds of a compound at the bench becoming a drug are incredibly small, e.g., for every 10,000 compounds that enter the drug discovery pipeline, only 250 will progress to pre-clinical development (2.5-5%); 5 move forward into human testing, Phase I studies (0.1-0.5%); and only a single compound will survive through Phase II and Phase III studies to be an approved drug (0.01%).

So this is a rare thing, and telaprevir is not just any drug. It will meet a significant unmet medical need. Anyway, forgive me for so much gratuitous backslapping, but I’m proud to have been part of the team — a great group of scientists, many of whom (including myself) no longer work at Vertex — who discovered the compound and brought it to clinical candidate status.

*Boceprevir is actually from the former Schering-Plough, which Merck acquired.
** Strictly speaking, boceprevir is the first approved HCV protease inhibitor and thus truly “first-in-class,” but I use the phrase collectively here, as the approvals were almost back-to-back.

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Well, I love that dirty water…Oh, Boston, you’re my home!

Or rather it will be soon (again).

Hello there. Doc Bushwell, effectively erstwhile bonobo-matriarch here with a bit of good news. Last Wednesday evening, I signed the written offer for a new job: that of regulatory medical writer at a major biotechnology company in Cambridge, MA with a tentative starting date of July 26. On Thursday, I quietly scuttled off at lunchtime to go pee in a cup for the pre-employment drug screen. On Friday, I gave 2 weeks notice to my current employer.

When I moved to New Jersey in 2004, I told myself that my long-term plans included moving back to the Boston area. So this is happening just a bit sooner. The family is gung-ho about returning even if the move will be a freakin’ nightmare. Well, most moves are like that.

I’ll miss certain things about Jersey: martinis at Mediterra in Princeton with my friends, ripe tomatoes, sweet corn and peaches (oh, those Jersey peaches!), the ability to visit NYC easily, and walks through the woods that border my home. My current employer, a small CRO that focuses on oncology clinical trials, provided excellent training for me, and I have considered these past two years with the company to be much like a post-doc. Nonetheless, whenever I left Boston after visits over these past six years, I always felt melancholy as if I were leaving my hometown to return to a place where I really did not quite belong. But now? Well, it feels like I am going home again: I’m shipping up to Boston!

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Survey: Depressed Americans prefer pills to therapy

This is not surprising. A Consumer Reports survey of over 1,500 Americans with clinical depression suggests that far more people embrace pills than embrace talk therapy, despite the fact that those who attended at least seven therapy sessions reported as much symptom relief as those who relied on drugs alone. Four in five respondents, in fact, replied that they would rather go the pharmacological route.

This is understandable, given that taking a pill as a lot less work and, in many cases, is a lot cheaper than visiting a therapist. But this doesn’t take into account efficacy, and many people have spent years trying to find an SSRI or other drug that produces the desired effects.

Of course, this is a false dichotomy, since many people on medication are also in therapy. But it’s clear that people are hungering for a magical solution to a complex problem, and it’s unlikely that clinically depressed people will ever fully return to baseline using pharmacotherapy alone.

Of ancillary note: More and more people who seek help for mental-health problems report anxiety as one of their symptoms, and the type of therapist people employ (psychiatrist vs. psychologist vs. social worker, etc.) does not appear to have an effect on the efficacy of therapy.

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I’d hate so see their idea of “artificial”

My mother takes a cholesterol-lowering supplement called Multi + CholestOff that is manufactured by a company called Nature Made. Under the name of the product on the package appears the claim “Lowers Cholesterol Naturally.” If you’re getting the idea that this product is being marketed as a pristine and healthier alternative to synthetic or “artificial” medications, great. That’s what Forbes Medi-Tech (the parent company of Nature Made) wants you to think, and they also want you to accept out of hand the premise that “natural” categorically equals better.

Now for a look at the ingredients: Read the rest of this entry »

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Congratulations, JoAnne Stubbe!

An e-mail this morning from one of my former Univ. of Wisconsin-Madison classmates informed me that JoAnne Stubbe, Novartis Professor of Chemistry, Professor of Biology at the Massachusetts Institute of Technology, and who was the first woman to achieve tenure in the biochemistry department at the UW-Madison, received the National Medal of Science from Barack Obama yesterday.

JoAnne is a fiercely brilliant woman who intimidated the bejeebus out of me when I was a fledgling grad student and later as a callow post-doc. She was one of five professors (including my advisor) who raked us over the coals during student research seminars. I also faced her wrath when I overtightened the valve to her lab’s French press. But later, when out and about in the real world, my encounters with Professor Stubbe were nothing but good. She’s funny, intense, and passionate about science. She’s a superb intellectual role model, and even though she was not my advisor, she nonetheless influenced me along with many of us in the biochem. department at the UW-Madison. Her award is a such fantastic and well-deserved achievement!

She was at the vanguard of women entering academia and industry in disciplines like chemistry and physics which were long dominated (and still dominated) by men, but these awards as well as the Nobels with 3 women winners in the sciences this year, including Elizabeth Blackburn and Carol Greider for telomeres/telomerase, indicate that “an old girls” network is forming at last.

Here’s a link to the article in the Boston Globe about JoAnne.

Her picture receiving the medal is here in the White House blog (scroll down) and below the cut is the press release (see bolded type a ways down for JoAnne’s award).

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Why Breathe When You Can Swallow?

From a recent ad spotted in Running Times magazine, we discover a way to get oxygen into the bloodstream of athletes without using the lungs. Yes, it’s SportsOxy Shot from Scientific Solutions LLC. They’re selling “super oxygenated” water that’s supposed to drastically improve athletic performance. A “serving” is 10 milliliters and it contains 15 volumes percent O2. Hmmm, a quick back-of-the-envelope calculation reveals something interesting. Let’s say we have a decent (though not elite) runner with a VO2max of 60 ml O2 per kg per minute. Further, let’s say that they’re running at an easy pace and using maybe 2/3 rds of their maximal O2 uptake and they’re kinda small, maybe 50 kg. That’s a per minute O2 intake of 2 liters. Why do I get that impression that swallowing 10 milliliters of “highly oxygenated” water isn’t going to have much of an effect over the course of even a short race, such as 1500 meters?
Oh, and a 500 milliliter bottle is only $60, on special. Stop by and order yours today, and while you’re at it, check out some of their other great “products”.

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This explains a lot: coffee consumption linked to hallucinations

A study out of Durham University (not a university in Durham, North Carolina, a fine institution in its own right) suggests that people who consume the equivalent of seven cups of instant coffee a day are three times more likely to hear things that aren’t there than those who consume little to no caffeine.

In the study, funded by the Economic and Social Research Council and the Medical Research Council, 200 students were asked about their typical intake of caffeine containing products, such as coffee, tea and energy drinks as well as chocolate bars and caffeine tablets. Their proneness to hallucinatory experiences, and their stress levels, were also assessed. Seeing things that were not there, hearing voices, and sensing the presence of dead people were amongst the experiences reported by some of the participants.

Seven cups sounds like a lot until you consider that, at least in the U.S., 1) seven cups of instant coffee is equivalent to about five cups of brewed coffee, and 2) a “cup” is considered to be 8 ounces, far less than those of us suckling at the teat of Dunkin’ Donuts and its cousins with their 24-ounce XL methylxanthine bombs will ever chug in a sitting. 40 ounces of brewed coffee a day is nothing to some of us. Fortunately, I remain firmly grounded in reality, although I’m a little annoyed that my keyboard won’t stop playing Herbie Hancock tunes every time I enter a blog post (and AC/DC whenever I rip into Concord Monitor commenters).

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Catching up with sports dopers: benzothiazepines

The drugs athletes use to gain an illegal edge in take one of two general forms: they are variants of (most often) steroids already known to, and tested for, by doping authorities, chemically modified to make them less detectable or undetectable in screenings; or they are drugs developed in order to treat familiar diseases, with their effects on strength, speed, and endurance being merely a happy and happenstance finding among “sports pharmacologists” who then deploy them well before testing authorities get wise.
The former “class” become more popular in the 21st century as technology on both the cheating and testing sides has become more elaborate–in the past, drugs use for doping were invariably drugs already on the market and developed for the purpose of treating illnesses. In the case of the latter, testers have an especially difficult job when the “drug” is actually a substance produced naturally in the body that has recently entered mass synthetic production thanks to recombinant technology. Perhaps the best-known example of the is erythropoetin (EPO), a hormone produced in the adrenal glands that stimulates the production of new red blood cells. Originally used to treat anemia, most often in people with chronic kidney disease or cancer, it quickly became a favorite of distance runners, Nordic skiiers, and cyclists because of its immediate and marked effects on aerobic capacity. It has spawned a number of synthetic cousins since the early 1990s, notably darbepoetin.

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Coked-up honeybees are dishonest

Honeybees are known for responding strongly to rewards, with foraging varieties performing a “dace” in response to a particularly good cache of pollen. Cocaine is a drug which lights up the reward centers in the human brain with aplomb. Considering these two factors in concert, a university researcher in Australia applied cocaine to the backs of honey bees to see what would happen.
The result: The affected bees returned to the hive and “danced” with unprecedented enthusiasm, conveying the idea that the pollen was much better than it actually was.
Then again, maybe if bees could talk as well as they can dance they would have simply told their mates, “Dudes! See that really great big tall enormous giant with the Q-tip and no wings? Go check him out, ’cause he’s got some really good shit!”

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Personalized Pharmaceuticals

Finally! A prescription medication tailor-made for me!
From the makers of Damitol and Fukitol, here is…

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Dropsy, Digitalis and Darwin (Erasmus, that is)

So. It’s National Poetry Month. Type that key phrase into the “search” query field on the main page of SB, and you’ll find that April brings forth a veritable poetry slam among Science Bloggers. In this fine tradition, I will don my black trousers, turtleneck, jaunty (but dirty) beret, take a drag from my half-smoked Gauloise ciggie and go Boho here with a selection from the original Botanical Pornographer, Erasmus Darwin, Charles’ grandfather. Today, I have chosen his ode to digitalis. Cue bongo drums.

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Judah Folkman: 1933-2008

Judah Folkman, a most extraordinary scientist, died Monday at age 74. Orac (Respectful Insolence) posted a fitting tribute which I highly recommend. See also Alex’s (Daily Transcript) entry and this New York Times article.
12-folkman.jpg
Thanks to the intricate academic vascular network between Harvard and Boston biotech, Folkman visited the company in Cambridge MA for which I previously worked. His seminar enthralled us and exemplified his ability to communicate so effectively. Folkman’s persistent championship of the anti-angiogenic drugs born of his research illustrates his belief in his work and also the challenges of bringing novel chemical entities into the clinic. Development of orally administered small molecule antagonists of angiogenesis followed the entry of Avastin, Genentech’s monoclonal antibody therapeutic, into the clinical sphere. Astra-Zeneca’s Iressa and Pfizer’s Sutent, which interfere with angiogenesis through inhibition of key receptor tyrosine kinases (epidermal growth factor receptor for Iressa; multiple tyr kinases for Sutent), were discovered by building upon Folkman’s pivotal discoveries. See this diagram from Nature Reviews Drug Discovery for the simplified sites of interaction for these drugs. Thanks to Dr. Folkman, angiogenesis remains a continued source of interest for the discovery of new chemotherapeutics.
Folkman was interviewed by NOVA in 2001. A film clip may be found within that site.
Folkman was one of those scientific giants who was also a charismatic and accessible man. His passing is a tremendous loss to the biomedical community, but he has left us with a rich legacy.

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The Scent of a Man…or a Monkey.

I previously confessed that I subscribe to that glossy hardcopy glut of advertising called Vanity Fair. Invariably, the mag contains photo spreads of ripple-ab’ed dudes hawking various men’s cologne. All this to mask delicious or stinky or neutral 5alpha-androst-16-en-3-one (androstenone); based on one’s genetic variation in the olfactory receptor that binds this steroid, it will smell sweet or icky or not at all. Razib at Gene Expression already covered the recent article in Nature – please see a world of sensory difference.

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The (NP)Y’s and Wherefores of Stress and Obesity

When I find myself in times of trouble
Ben and Jerry’s comes to me
Snarfing Chunky Monkey so sweetly, so sweetly.

When stressed, some folks barely eat and consequently lose weight. Others, including myself, reach for high-fat-high-sugar (HFS) foods in an attempt to ameliorate the angst. Although the connection between stress and overeating is not fully understood, the evidence until recently focused on centrally acting (brain & spinal cord) mechanisms, e.g., hypothalamic control of food consumption and metabolism.
However, Lydia Kuo et al. (1) reported recently in Nature Medicine that stress-triggered release of neuropeptide Y (NPY) can stimulate angiogeneis (formation of new blood vessels) in the periphery, i.e., other places in the body than the brain and spinal cord. The researchers also demonstrated that NPY stimulates creation and differentiation of new fat cells (adipogenesis). NPY evidently binds to its receptor (or one of its receptors), NYP2R – a G-protein coupled receptor, and gets the big fat ball rolling.
More below the corpulent fold…

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The (NP)Y’s and Wherefores of Stress and Obesity

When I find myself in times of trouble
Ben and Jerry’s comes to me
Snarfing Chunky Monkey so sweetly, so sweetly.

When stressed, some folks barely eat and consequently lose weight. Others, including myself, reach for high-fat-high-sugar (HFS) foods in an attempt to ameliorate the angst. Although the connection between stress and overeating is not fully understood, the evidence until recently focused on centrally acting (brain & spinal cord) mechanisms, e.g., hypothalamic control of food consumption and metabolism.
However, Lydia Kuo et al. (1) reported recently in Nature Medicine that stress-triggered release of neuropeptide Y (NPY) can stimulate angiogeneis (formation of new blood vessels) in the periphery, i.e., other places in the body than the brain and spinal cord. The researchers also demonstrated that NPY stimulates creation and differentiation of new fat cells (adipogenesis). NPY evidently binds to its receptor (or one of its receptors), NYP2R – a G-protein coupled receptor, and gets the big fat ball rolling.
More below the corpulent fold…

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DNA meets MLB!

Commenting on my slap at Bud Selig, Saint Gasoline brings up a good point about the futility of trying to account for the “tainting” by drug use of records in baseball.
I figure that most of the people ostensibly agitating for asterisks next to new records don’t really want to see them used, recognizing that even staunch opponents of performance-enhancing drugs can’t avoid the reality of a slippery slope (i.e., how do we know people who were never caught before testing were really clean).

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Spectators and mayhem at the TdF

It’s great that the Tour de France is enormously popular in Europe and attracts about 7.8 gazillion spectators to the route’s roadsides. The only problem is that they are notoriously bad about keeping out of the way, with the unavoidable consequence that they can and indeed do have an impact on the outcome of the race itself.
The eventual winner of Friday’s 18th stage, Sandy Casar, crashed in the early going after an unleashed dog — maybe a drug-sniffing canine, who knows — ran into the road (video). Hours later, the man currently in second place in the overall standings, Cadel Evans of Australia, ran into a spectator near the finish but maintained control of his bike.
Casar’s tumble was, in fact, the second dog-related crash of this year’s Tour. German rider Marcus Berghardt nailed a dog at about 40 km/hr in the ninth stage; I include the video below only because the rider and the dog were both okay (and the mutt, which took a seat to the head as well as a wheel to the flank, not only walked away but was even wagging its tail). Watch the front wheel of the bike crumple on impact:

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Moreni flunks drug test; Cofidis “invited to leave” Tour

Remember the beleaguered medical student in the film Gross Anatomy who was “invited to leave” by the school administration after a series of breakdowns? Perhaps the Tour de France officials are taking a cue from the movie’s dialouge, extending a warm invitation to the Cofidis squad to withdraw from the race after one of its riders, Cristian Moreni, submitted a blood sample that turned up positive for testosterone. The sample was taken after the 11th stage last week.
Testosterone — like many chemicals athletes use to cheat — is a naturally occurring substance in both male and female bodies, so unlike, say, methamphetamine or ephedrine, its presence is not verboten per se. The test actually assays the ratio between testosterone and a metabolite, epitestosterone; a ratio exceeding a certain threshold signifies the introduction of exogenous testosterone into the system and results in the sample being flagged positive.
The Tour is scheduled to end Sunday, but if the disqulification rate picks up much more it may end sooner. On Tuesday, the Astana team withdrew after promonent rider Alexandre Vinokourov tested psotive for blood doping, or using red blood cells “donated” by someone else, frozen, and stored for later use. Race leader Michael Rasmussen of Denmark has worn the yellow jersey for over a week now but is toiling under a cloud of suspicion andwas booed as he won the 16th stage today.
VeloNews.com has a handy article by a medical doctor explaining the basics of blood doping and the test(s) used to detect it. How many sports wind up with their leading publications being more or less compelled to explain exactly how its participants flaunt the rules, so that spectators can have a complete view of what they’re seeing?

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