The percentage of the U.S. population taking at least one prescription drug during the past 30 days increased from 38% in 1988–1994 to 48% in 2005–2008. During the same period, the percentage taking three or more prescription drugs nearly doubled, from 11% to 21%, and the percentage taking five or more drugs increased from 4% to 11%. These data come from the CDC “Health, Unites States, 2011″ report (find it here).

Meanwhile, the prevalence of heart disease, which is the leading cause of death in the U.S., remained steady from 1999–2000 to 2009–2010 among adult women in all age groups, and among men 45–74 years of age. Among men 75 years of age and over, prevalence rose from 39% in 1999–2000 to 45% in 2009–2010.

There goes my rationale for taking statins to lower my risk of heart attack! It seems that the drug industry is not as successful in improving our health as it claims to be.

And new drugs aimed at lowering the risk for heart disease currently being developed may be effective in achieving “surrogate endpoints” in clinical trials but not effective in reducing risk.

That was the takeaway from a new study published online recently in The Lancet. That study provided evidence that increasing the level of HDL (“good cholesterol”) does not lead to less risk for heart disease (see “HDL hypothesis is on the ropes right now“).

That’s not good news for companies that are actively developing and testing drugs that raise HDL — even if these drugs succeed in that goal they are not likely to help prevent heart disease.

There’s lots of other interesting data in the CDC report. I’ve gathered my favorite charts into the infographic shown here (click here for an enlarged view).

For those of you interested in the recent work on the diversity of different cancer cell genotypes inside single tumors, there’s a review out that covers the field well. The authors also go into some of the major unanswered questions: does having a tumor cell population with a lot of genetic diversity correlate with a poor prognosis for treatment? Can small populations of potentially troublesome cells be identified ahead treatments that might give them too free a field to work in? Can the huge genetic diversity be reduced to a more manageable set of practical phenotypes, to make therapeutic recommendations? This will keep everyone busy for a long time to come.

I’ve read a couple of medical papers recently that show how tricky it is to draw conclusions on what patients would be best helped by a specific therapy. Many of you will have seen the paper in The Lancet on the use of statins in low-risk patients. This isn’t something you’d necessarily think would do much good – it all depends on what the benefits are, at the margin, of lowering LDL. But the results appear surprisingly strong:

In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.

A note to the conspiratorially minded, should any such come across this: it’s worth noticing that this “maybe everyone should take statins” result comes after the major ones have gone off patent. Pfizer, Merck et al. would have greatly enjoyed this recommendation had it occurred ten years ago, but it didn’t (and probably couldn’t have, since we didn’t have as much data as we do now).

Now to another (often related) disease, type II diabetes. It’s been found that bariatric surgery improves glycemic control in the very obese patients who are candidates for the procedure. And that makes sense – obesity is absolutely a risk factor for type II in the first place. But as more and more of these surgeries are being done, something odd is becoming apparent:

Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of ‘metabolic surgery’ to treat diabetes has taken a big step forward.

Why this happens is a very good question indeed. Patients seem to benefit greatly within the first two weeks after gastric bypass surgery, well before any significant weight loss has occurred. My first guess is that it’s something to do with secretion of hormones from the gut itself, and you’d also have to think that nutrient sensing gets profoundly altered. It’s not going to be easy to turn this into an approved therapy, though. Running randomized clinical trials for dramatic surgical procedures (versus noninvasive care) is difficult, as you’d imagine:

Despite these compelling clinical observations, RCTs of surgery versus nonsurgery are sorely needed. Ample precedents exist wherein RCTs reversed longstanding paradigms derived from nonrandomized clinical trials. Some of the best evidence in bariatric surgery, from the Swedish Obese Subjects study (a long-term observation of various operations versus conventional care), is prone to allocation bias because participants were not randomized. Subjects who actively chose surgery may be more motivated overall and generally take better care of themselves. The NIH is unlikely to reconsider its guidelines without pertinent RCTs, and insurance companies are unlikely to pay for operations that are not NIH-sanctioned.

Both of these results point out the completely nonlinear nature of living systems. It can work for good, as in these cases, or for bad. Alzheimer’s, the subject of yesterday’s post, is a perfect example of the latter: one protein, out of perhaps a few million, has one of its hundreds of amino acids changed in one small way on its side chain. And it’s a death sentence. Good to know that things can work in the other way once in a while.

The failure of Roche’s dalcetrapib has a lot of people wondering just what’s going on with HDL as a cardiovascular drug target. And this isn’t the first time – there have been a number of puzzling findings in the lipoprotein field that point out to us that we don’t know nearly as much about this area as we might think. Many promising therapeutic ideas in it have turned out disastrously.

Now there’s a new paper in The Lance that underscores this, and how. The authors have done large genome-wide association studies looking for polymorphisms that affect lipoproteins, and they’re following those up with clinical data on cardiovascular outcomes. Untangling the effects of HDL, LDL, triglycerides and other factors isn’t easy, but they did find one mutation that appears to raise HDL alone. Looking at the people carrying that one, they find that there’s no amelioration of risk in them at all. That’s as opposed to the mutations that lowered LDL levels, which were consistently associated with lower risks.

This doesn’t (necessarily) mean that HDL is useless as a predictor of cardiovascular risk, but it definitely means that it isn’t as simple as “HDL = Good Cholesterol!”. What this means for things like CETP inhibition is anyone’s guess.

Just a note: the Breslow origins-of-chirality paper, also known more widely (thanks to some bizarre PR work at the ACS) as the “alien dinosaur” paper, has been withdrawn, and on the correct grounds. The pun in the headline is intended.

Alzheimer’s disease is in the news, as the first major preventative drug trial gets underway. I salute the people who have made this happen, because we’re bound to learn a lot from the attempt, even while I fear the chances for success are not that good.

A preventative trial for Alzheimer’s would, under normal circumstances, be a nightmarish undertaking. The disease is quite variable and comes on slowly, and it’s proven very difficult to predict who might start to show symptoms as they age. You’d be looking at dosing a very large number of people (thousands, even tens of thousands?) for a very long time (years, maybe a decade or two?) in order to have a chance at statistical significance. And you would, in the course of things, be giving a lot of drug to a lot of people who (in the end) would have turned out not to need it. No, it’s no surprise that no one’s gone that route.

But there’s a way out of that impasse: find a population with some sort of amyloid-pathway mutation. Now you know exactly who will come down with symptoms, and (unfortunately) you also know that they’re going to come down with them earlier and more quickly as well. There are several of these around the world; the “Swedish” and “Dutch” mutations are probably the most famous. There’s a Colombian mutation too, with a well-defined patient population that’s been studied for years, and that’s where this new study will take place.

About 300 people will be given an experimental antibody therapy to amyloid protein, crenezumab. This was developed by AC Immune in Switzerland and licensed to Genentech, and is one of many amyloid-targeted antibodies that have come along over the years. (The best-known is bapineuzumab, currently in Phase III). Genentech (Roche) will be putting up the majority of the money for the trial ($65 million, with $16 million from the NIH and $15 million in private foundation money). Just in passing, weren’t some people trying to convince everyone a year ago that it only costs $43 million total to develop a new drug? Har, har.

100 people with the mutation will get the antibody every two weeks, and 100 more will get placebo. There are also 100 non-carriers mixed in, who will all get placebo, because some carriers have indicated that they don’t want to know their status. Everyone will go through a continuing battery of cognitive and psychological tests, as well as brain imaging and a great deal of blood work, which (if we’re lucky) could furnish tips towards clinical biomarkers for future trials.

So overall, I think that this trial is an excellent idea, and I very much hope that a lot of useful information comes out of it. But I’ve no firm hopes that it will pan out therapeutically. This will be a direct test of the amyloid hypothesis for Alzheimer’s, and although there’s a tremendous amount of evidence for that line of thought, there’s a lot against it as well. Anyone who really thinks they know what will happen in this situation hasn’t thought hard enough about it. But that’s the best kind of experiment, isn’t it?

How much do we really know about what small drug molecules do when they get into cells? Everyone involved in this sort of research wonders about this question, especially when it comes to toxicology. There’s a new paper out in PLoS One that will cause you to think even harder.

The researchers (from Princeton) looked at the effects of the antidepressant sertraline, a serotonin reuptake inhibitor. They did a careful study in yeast cells on its effects, and that may have some of you raising your eyebrows already. That’s because yeast doesn’t even have a serotonin transporter. In a perfect pharmacological world, sertraline would do nothing at all in this system.

We don’t live in that world. The group found that the drug does enter yeast cells, mostly by diffusion, with a bit of acceleration due to proton motive force and some reverse transport by efflux pumps. (This is worth considering in light of those discussions we were having here the other day about transport into cells). At equilibrium, most (85 to 90%) of the sertaline that makes it into a yeast cell is stuck to various membranes, mostly ones involved in vesicle formation, either through electrostatic forces or buried in the lipid bilayer. It’s not setting off any receptors – there aren’t any – so what happens when it’s just hanging around in there?

More than you’d think, apparently. There’s enough drug in there to make some of the membranes curve abnormally, which triggers a local autophagic response. (The paper has electron micrographs of funny-looking Golgi membranes and other organelles). This apparently accounts for the odd fact, noticed several years ago, that some serotonin reuptake inhibitors have antifungal activity. This probably applies to the whole class of cationic amphiphilic/amphipathic drug structures.

The big question is what happens in mammalian cells at normal doses of such compounds. These may well not be enough to cause membrane trouble, but there’s already evidence to the contrary. A second big question is: does this effect account for some of the actual neurological effects of these drugs? And a third one is, how many other compounds are doing something similar? The more you look, the more you find. . .

This fine reagent was mentioned here (disparagingly) in the comments the other day, and I knew that it was time to add it to the list. I’ve had some other selenium entries before, and they’re all here for the same reason: their unsupportable stenches. Everyone, even people who’ve never had a chemistry class in their lives, knows that sulfur compounds are stinky, of course, but it’s a problem that continues as you move down Group XVI of the periodic table.

And it’s not like plain phenol itself has no odor. It’s strong, penetrating, and completely unmistakable. As soon as I get a whiff of the stuff, I’m immediately transported back to the Verser Clinic, the small hospital in the town I grew up in back in Arkansas. Phenol smells like an old-fashioned medical office; it was used for many years as a disinfectant (and was, in fact, introduced as such by Joseph Lister himself). If you move it down a notch to sulfur, you get thiophenol, which is easy to describe: burning rubber – the pure, potent, platonic ideal of burning rubber, bottled up and daring you to open the cap. I can’t say that I won’t work with thiophenol, since I have (very much to my regret, at times), but I’ve used it most reluctantly, and probably haven’t touched it in at least fifteen years.

Ah, but move down one more element and you have selenophenol, and that’s a more exotic reagent. I’ve never seen any, and after reading the descriptions, I never want to. Actually, let me take that back: I’d look at some from the other end of the lab. What I never want to do is open any of it up. The chemical literature has numerous examples of people who are at a loss for words when it comes to describing its smell, but their attempts are eloquent all the same. A few years ago, Gaussling at the Lamentations on Chemistry blog referred to it as “The biggest stinker I have run across. . .Imagine 6 skunks wrapped in rubber innertubes and the whole thing is set ablaze. That might approach the metaphysical stench of this material.” So we’ll start with that.

I believe that this lovely compound is commercially available (if you’re anywhere close to anyone making it, you’ll know about it). But should you wish to prepare it with your own hands, do violence to your own schnozz, and drape yourself out of your own window while you throw up into your own rhododendrons, feel free to use this reliable preparation from Organic Syntheses, circa 1944. This features the note that “it is frequently advisable to work with [selenium compounds] on alternate days”, which I suppose is to give them time to work their way out of your nasal passages.

I’m not so sure. When I was a teaching assistant in grad school, I taught three labs a week one semester, and one of those labs, damn it all, was the phenyl Grignard reagent. We had them making it in diethyl ether, outside of the small and inadequate fume hoods, and the solvent fumes were fit to strip paint. By the end of the Monday lab, I was well saturated with ether and had a terrible headache, which returned as soon as I caught my first whiff of the stuff on Tuesday afternoon. I barely made it through that lab, mostly by holding my breath and using a lot of hand gestures, and I took the opportunity on Wednesday to get as much fresh air as I could. But when I came back for the Thursday session, the first first wave of ether vapor washed over me and nearly stretched me out on the tiles. I taught the entire lab from the hallway, shouting and waving like Monty Python’s “Semaphore Version of Wuthering Heights”. So in my mind, the choice between getting these things over with and stretching them out is still not settled.

That Org Syn prep also notes that it can produce small amounts of hydrogen selenide, which is very toxic indeed (and will give you a sore throat, too, apparently, before it kills you). This luckless graduate student from the 1920s got to experience both of these bracing selenium room fresheners in the course of his work:

Berzelius described the poisonous effect of hydrogen selenide quite impressively; “In order ta get acquainted with the smell of this gas I allowed a bubble not larger than a pea to pass into my nostril ; in consequence of its smell I so completely loss my sense of smell for several hours that I could not distinguish the odor of strong ammonia even when held under my nose. My sense of smell returned after five or six hours, but severe irritation of the mucous membrane set in and persisted for a fortnight’ The writer has been working on the gas for some time and was also quite seriously affected once, the injury persisting for many days. That it is more poisonous than the hydrogen sulphide is well known.”

So you have that to look forward to on your way to selenophenol. And at your destination? Assuming your nose is still attached to your face, you’ll experience what few chemists ever have. I’ll let this 1908 report from Wisconsin take over:

When benzeneselenonic acid in solution is treated with reducing agents such as hydrogen sulphide, sulphur dioxide, or, best, with zinc and hydrochloric, acid selenophenol is obtained as a yellow oil with an overpowering and most nauseating odor. . .The odor of diphenyl diselenide is extremely disagreeable but is not nearly so bad as that of selenophenol.

. . .The effect of selenophenol on the skin is very similar to that of thiophenol, forming blisters which itch intensely. After a time, these dry up, the skin scales off, and there appears to be a deposit of red selenium beneath it. The odor of selenophenol is very penetrating, and is nauseating beyond description.

Gloves, man, gloves. Unless, of course, you wish to be tattooed with elemental selenium while being nauseated beyond description. Should this be your idea of a fun Saturday night, I will not stand in your way.

Now here’s a worrisome thought, if you’re doing kinase research. A tyrosine kinase inhibitor in the clinic against Bcr-Abl, bosutinib (SKI-606), is also being used as a research tool in a number of academic groups. But they’re probably not using what they think they’re using.

This article has the details. The compound has a dichloromethoxy aryl group hanging off of it, and apparently someone has been making (or made one good-sized batch of) the wrong isomer. Instead of 2, 4-dichloro-5-methoxy, many commercial samples appear to be 3,5-dichloro-4-methoxy. This got noticed at first by inspection of an X-ray structure deposited in the Protein Data Bank, 3ZZ2, from a group at Oxford. A postdoc at Stanford saw that something was off, and at the same time, he was having trouble matching his own X-ray data with the known structure of the compound.

The explanation wasn’t what anyone wanted to hear, for sure. The two groups had purchased their material years apart, from different vendors. The count of vendors selling the wrong material is now up to thirteen and climbing. That link also suggests a possible earlier source of the problem: some of the commercial supplies of 2,4-dichloro-5-methoxy aniline are not the right material. Whoever made this bosutinib may well have thought that they were right on target.

Odds are, some batch of the wrong stuff has been resold through the supplier community since at least 2006 – this sort of thing goes on all the time. But the tricky part here is that LC/MS wouldn’t have told you that there was a problem, unless you had an authentic sample to check the retention times (which would have been pretty darn close, anyway, I’d guess). The mass is, of course, the same. And the NMRs of the authentic and mis-labeled stuff would be different, but not on casual inspection, for sure (same number of aryl protons). No, I would have let this stuff through, I’ve no doubt about that. Makes a person wonder what else on the shelf is the wrong material, doesn’t it?

A reader sends along this query, which I thought asked a very useful question:

“. . .as a member of a growing biopharma company I am tasked with evaluating the effectiveness of industrial post-docs from both a business perspective and the post-doc’s experience. Specifically, we are considering adding one for a short-term (2yr) to add headcount to a project. This adds resources without the long term commitment and also gives the scientists on site a chance for a paper they otherwise might not have time to work on. The candidate obviously gets a well-paid post-doc experience, and an industrial foot in the door. But, does this model work? I imagine that if it were that cut and dried you would see more of them.”

Good point. Industrial post-docs are still relatively rare, although I’ve certainly seen a few. Come to think of it, though, those were mostly in biology, as opposed to chemistry. So, what do people think? From my end, I’d say that traditionally, companies have felt that temporary positions are best filled with experienced temporary employees, who presumably don’t have to be trained as much. And if you’re going to hire someone to learn the ropes, they might as well be good enough to be brought in as a full-time employee.

From the other end, an industrial post-doc has always been seen as less prestigious than an academic one, and there are some hiring managers who probably don’t know what to think when one shows up on a c.v. There’s often a feeling that if the person did a really good job during the post-doc that the company would have tried to offer them something permanent. And since they didn’t, well. . .

Even so, it does seem as if there are situations where an industrial post-doc could be a good fit, and in today’s job market, anything looks good. Anyone out there experienced this, from either end?