About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
June 29, 2012
Has there ever been a less structurally appealing class of drugs than the cholesteryl ester transfer protein (CETP) inhibitors? Just look at that bunch. From left to right, that's Pfizer's torcetrapib (which famously was the first to crash and burn back in 2006), Roche's dalcetrapib (which was pulled earlier this year from the clinic, a contributing factor to the company's huge recent site closure), Merck's anacetrapib (which is forging on in Phase III), Lilly's evacetrapib (which when last heard from was also on track to go into Phase III), and a compound from Bristol-Myers Squibb, recently published, which must be at least close to their clinical candidate BMS-795311.
Man, is that ever an ugly-looking group of compounds. They look like fire retardants, or something you'd put in marine paint formulations to keep barnacles from sticking to the hull. Every one of them is wildly hydrophobic, most are heavy on aromatic rings, and on what other occasion did you ever see nine or ten fluorines on one drug molecule? But, as you would figure, this is what the binding site of CETP likes, and this is what the combined medicinal chemistry talents of some of the biggest drug companies in the world have been driven to. You can be sure that they didn't like it, but the nice-looking compounds don't inhibit CETP.
Will any of these fancy fluorocarbon nanoparticles make it through to the market, just on properties/idiosyncratic toxicity concerns alone? How do their inhibitory mechanisms differ, and what will that mean? Is inhibiting CETP even a good idea in the first place, or are we finding out yet more fascinating details about human lipoprotein handling? Money is being spent, even as you read this, to find out. And how.
+ TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology
There are a number of structures that I've never been quite able to make up my mind about in medicinal chemistry. One of those is the pyridine N-oxide.
You really don't see those in drugs (at least, no examples come to mind), but you don't see many people trying to advance them as drugs, either. Note: the first comment points out the two key examples I'd forgotten: librium and minoxidil. Once in a while they turn up in the literature, often never to be seen again. I believe that one problem with them is that they present in a living system as mild oxidizing agents, which is the sort of thing that cells try to avoid, and I can't imagine that their pharmacokinetics are very appealing either. There are quite a few pyridine derivatives that are turned into their N-oxides on the way to being excreted, which makes you think that bringing one in from the the start is greasing the skids for fast clearance. But I've never seen one dosed, so how would I know for sure?
These thoughts are prompted by this paper from J. Med. Chem., which has an even stranger-looking benzotriazine bis-oxide. These compounds seem quite active against drug-resistant tuberculosis strains (and it's always good to see something that can kill those guys off), but I'll watch with interest to see if they can be developed into drugs. Anyone else out there ever had the nerve to push an N-oxide forward?
+ TrackBacks (0) | Category: Life in the Drug Labs
June 28, 2012
If you're looking for an R. B. Woodward-themed decoration for you lab, look no further: Chemjobber has you covered.
+ TrackBacks (0) | Category: Blog Housekeeping
Over at Forbes, Matthew Herper has some thoughts now that the major parts of the Affordable Care Act have been upheld. Among them is this on its effect on the pharma business:
Will the law actually benefit some drug companies? Many in the drug business have expressed regret about the decision to back the Affordable Care Act, even blaming former Pfizer chief Jeffrey Kindler, a Democrat, for having pushed a deal through. I think that some of this opposition is based on outdated thinking that says that even though the government already pays for a lion’s share of health care spending through Medicare and Medicaid, giving it even more control will eventually create price controls like in Europe.
This made sense when the industry made all of its money selling mass market pills such as Lipitor and Plavix, both now off-patent. But the model for many new cancer drugs (the biggest category in drug company pipelines) and for drugs for rare diseases is that the companies charge a price no individual can pay, and then try to get insurers and governments to pay for them. This is the basic strategy taken by companies like Alexion, Biomarin, and the Genzyme division of Sanofi, all of which charge hundreds of thousands of dollars per patient per year for there medicines. Getting more people insured is good for these companies. Right now Alexion and Biomarin are down, which makes little sense. Fundamentally, the success of the drug industry depends on inventing new medicines; at most, the law is neutral. . .
We'll see. I think that the high-price/low-patient-population strategy that Herper refers to will be up for revision at some point, and perhaps sooner than we expect. One of the selling points of the ACA/Obamacare was that it would (somehow) contain costs, and I still have a lot of trouble believing that it will do anything of the kind. If (when?) we find that we're still spending piles of money on health care, one of the more politically popular ways to cut costs (or at least look as if you're cutting costs) will be to go after therapies that cost six figures a year.
And this could get tricky, because any cancer drugs that are actually effective are likely to be so only for small populations (the people who have tumors that are driven by one treatable mutation, as opposed to a swarm of genomically unstable cells that can mutate their way out of attempts to shut them down). The more we learn about which drugs to give to which patients, the smaller the treatable population gets for any individual drug, and the higher the price. These lines have been heading for an intersection for some time now, and I don't see how the health care law will keep things from getting messy.
+ TrackBacks (0) | Category: Business and Markets | Cancer | Regulatory Affairs
You'll remember the life-extending fullerenes paper that I blogged about here, and the various problems with it that sharp-eyed readers here spotted. (These drew comments from the lead author here and here). Now the journal has issued a correction that covers some of these issues, along with the following Editor's Note:
It should be noted that one of these errors, referring to the inadvertent duplication of the same image within two panels of Fig 4, was pointed out to the Editor-in-Chief by several readers. The authors contacted the Editor-in-Chief with an explanation of this error and an error in Figure 3 before he requested an explanation from the authors. This paper draws conclusions that appear counter-intuitive. The Editor-in-Chief received two very detailed reports from referees who indicated that the methodology appeared sound and they both recommended acceptance after some revision. Neither referee nor the Editor-in-Chief noticed either error, and the revised paper was published. Due consideration has been given to the potential effect of these errors on the overall results and conclusions drawn, and so it has been decided the conclusions are still valid. The authors have provided explanations of how the errors were made during the preparation of graphics and images.
The big questions remain - can these results be duplicated, and is anyone willing to try?
+ TrackBacks (0) | Category: Aging and Lifespan
There's no escaping politics and health care policy today. No matter what happens to the Affordable Care Act this morning (and no matter what you think of it either way), if you work in the drug industry, it's worth recalling that PhRMA (the big-company industry association) was very much in favor of the legislation. At least as it was finally passed, that is - there was a lot of quid-pro-quo-ing about drug reimportation and Medicare pricing, and agreement on those appears to have been PhRMA's price for supporting the bill. It was a deal that many objected to at the time, and in one of the few other times I've talked politics on this blog, I wondered if it was going to hold up even at that.
We know more of these details because of a set of e-mails and internal memos that show the group's agreement to advertise in favor of its passage, and to help senators and representatives who voted for it:
“As part of our agreement, PhRMA needs to undertake a very significant public campaign in order to support policies of mutual interest to the industry and the Administration,” according to a July 14, 2009, memo from the Pharmaceutical Research and Manufacturers of America. “We have included a significant amount for advertising to express appreciation for lawmakers’ positions on health care reform issues.”
The goal, the memo said, was to “create momentum for consensus health care reform, help it pass, and then acknowledge those senators and representatives who were instrumental in making it happen and who must remain vigilant during implementation.”
One of the vehicles for this was a coalition (involving PhRMA, the AMA, and others) called "Healthy Economy Now" (HEN), which appears to have been started by White House staffers. None of that is surprising or particularly unusual, but an unusual twist involves the White House's David Axelrod and his former advertising company AKPD. The company was still paying Axelrod at the time, and his son was working there, and it appears that they got a good part of the advertising business that PhRMA and the other funded:
A 2009 PhRMA memo also makes clear that AKPD had been chosen before PhRMA joined HEN. It's also clear that some contributors didn't like the conflict of interest. When, in July 2009, a media outlet prepared to report AKPD's hiring, a PhRMA participant said: "This is a big problem." Mr. Baldick advises: "just say, AKPD is not working for PhRMA." AKPD and another firm, GMMB, would handle $12 million in ad business from HEN and work for a successor 501(c)4.
Well, that's Washington, and no mistake. If you don't sit down at the table and cut a deal with these folks, this sort of thing happens to you. But no matter which way the Supreme Court goes this morning, or what parts of the bill might be struck down, it will affect the drug industry. From PhRMA's standpoint, the current legislation represents the fruits of a great deal of lobbying and arm-twisting (in both directions), a great deal of money, and a great deal of worry about future revenues. This work may be in danger of going partially or wholly for naught. We'll find out at 10 AM.
+ TrackBacks (0) | Category: Current Events
June 27, 2012
If you've been following Shire Pharmaceuticals and their Replagal saga, you've had quite a few twists and turns to keep you occupied. Replagal (agalsidase) is Shire's alternative to Fabrazyme, the Fabry's disease therapy from Genzyme, and during Genzyme's protracted manufacturing troubles, Shire was only to glad to step up in the market in the US. (Replagal hadn't been approved here, but had been on the market in Europe for some years).
So back in March, it was quite a surprise when the FDA turned down Shire's application. And details of why this happened have been scarce - until now? BioCentury is out with a very interesting story, based on what they say is "an unsolicited package of documents that are labeled as FDA briefing materials" from an anonymous source.
If these are on the level, the FDA seems to have had concerns that Replagal's physical characteristics have changed over the years, due to changes in manufacturing (most specifically, the switch to a bioreactor from roller bottles and the use of a different purification method). The content of sialic acid and mannose-6-phosphate, among other factors, seems to be an issue, and cellular uptake of the final product may have drifted downwards. The FDA seems to have decided that the only way to answer such questions was in the clinic, and that's when Shire seems to have balked.
No one at Shire or the FDA would comment on the authenticity of the documents, as Biocentury says, no one has taken the opportunity to dispute them, either. You wonder just how they walked out of the FDA. . .
+ TrackBacks (0) | Category: Regulatory Affairs
A lot of natural product structures have been misassigned over the years. In the old days, it was a wonder when you were able to assign a complex one at all. Structure determination, pre-NMR, could be an intellectual challenge at the highest level, something like trying to reconstruct a position on a chess board in the dark, based on acrostic clues in a language you don't speak. The advent of modern spectroscopy turned on the lights, which is definitely a good thing, but many people who'd made their careers under the old system missed the thrill of the old hunt when it was gone.
But even now, it's possible to get structures wrong - even with high-field 2-D NMR, even with X-ray spectroscopy. Natural products can be startlingly weird by the standards of human chemistry, and I still have a lot of sympathy for anyone who's figuring them out. My sympathy goes only so far, though.
Specifically, this case. I have to agree with the BRSM Blog, which says: "I have to say that I think I could have done a better job myself. Drunk." Think that's harsh? Check out the structures. The proposed structure had two napthalenes, with two methoxys and four phenols. But the real natural product, as it turns out, has one methoxy and one phenol. And no napthyls. And four flipping bromine atoms. Why the vengeful spirit of R. B. Woodward hasn't appeared, shooting lightning bolts and breaking Scotch bottles over people's heads, I just can't figure.
+ TrackBacks (0) | Category: Analytical Chemistry | Chemical News | Natural Products
June 26, 2012
Big news, and unfortunate news for the New Jersey end of the pharma business: Roche is closing down their entire site in Nutley. That's a loss of 1000 jobs, and an end to a research site that's been going since the 1930s and which was once a huge presence in the R&D world. The research is going to be picked up by Roche sites in Germany and Switzerland. The company says that it's going to open a smaller translational research center, though:
A location is being identified on the East Coast to focus on translational clinical research to support Roche US-based clinical trials and early development programs, support and maintain Roche interactions with the U.S. Food and Drug Administration (FDA), and enhance Roche's collaborations with US based partners, such as academic institutions and biotech companies. This new center is expected to host around 240 employees.
That sounds like a Boston/Cambridge deal to me, but we'll see. For now, we have a very large closing indeed.
+ TrackBacks (0) | Category: Business and Markets
Nature Reviews Drug Discovery has an article on the current state of drug development, looking at what's expected to be launched from 2012 to 2016. There's a lot of interesting information, but this is the sentence that brought me up short: "the global pipeline has stopped growing". The total number of known projects in the drug industry (preclinical to Phase III) now appears to have peaked in 2009, at just over 7700. It's now down to 7400, and the biggest declines are in the early stages, so the trend is going to continue for a while.
But before we all hit the panic button, it looks like this is a somewhat artificial decline, since it was based on an artificial peak. In 2006, the benchmark year for the 2007-2011 cohort of launched drugs, there were only about 6100 projects going. I'm not sure what led to the rise over the next three years after that, but we're still running higher. So while I can't say that it's healthy that the number of projects has been declining, we may be largely looking at some sort of artifact in the data. Worth keeping an eye on.
And the authors go on to say that this larger number of new projects, compared to the previous five-year period, should in fact lead to a slight rise in the number of new drugs approved, even if you assume that the success rates drop off a bit. They're guessing 30 to 35 launches per year, well above the post-2000 average. Peak sales for these new products, though, are probably not going to match the historical highs, so that needs to be taken into account.
More data: the coming cohort of new drugs is expected to be a bit more profitable, and a bit more heavily weighted towards small molecules rather than biologics. Two-thirds of the revenues from this coming group are expected to be from drugs that are already in some sort of partnership arrangement, and you'd have to think that this number will increase further for the later-blooming candidates. The go-it-alone blockbuster compound really does seem to be a relative rarity - the complexity and cost of large clinical trials, and the worldwide regulatory and marketing landscape have seen to that.
As for therapeutic area, oncology has the highest number of compounds in development (26% of them as of 2011). It's to the point that the authors wonder if there's an "oncology bubble" on the way, since there are between 2 and 3 compounds chasing each major oncology target. Personally, I think that these compounds are probably still varied enough to make places for themselves, considering the wildly heterogeneous nature of the market. But it's going to be a messy process, figuring out what compounds are useful for which cases.
So in the near term, overall, it looks like things are going to hold together. Past that five-year mark, though, predictions get fuzzier, and the ten-year situation is impossible to forecast at all. That, in fact, is going to be up to those of us doing early research. The shape we're in by that time will be determined, perhaps, by what we go out into the labs and do today. I have a tool compound to work up, to validate (I hope) an early assay, and another project to pay attention to this afternoon. 2022 is happening now.
Update: here are John LaMattina's thoughts on this analysis, asking about some things that may not have been taken into account.
+ TrackBacks (0) | Category: Business and Markets | Drug Development
June 25, 2012
Here's another reminder that we don't know what a lot of existing drugs are doing on the side. This paper reports that the kinase inhibitor Nexavar (sorafenib) is actually a pretty good ligand at 5-HT (serotinergic) receptors, which is not something that you'd have guessed at all.
The authors worked up a binding model for the 5-HT2a receptor and ran through lists of known drugs. Sorafenib was flagged, and was (experimentally) a 2 micromolar antagonist. As it turns out, though, it's an even strong ligand for 5-HT2b (57 nM!) and 5-HT2c (417 nM), with weaker activity on a few other subtypes. This makes a person wonder about the other amine GPCR receptors, since there's often some cross-reactivity with small molecule ligands. (Those, though, often have good basic tertiary amines in them, carrying a positive charge under in vivo conditions. Sorafenib lacks any such thing, so it'll be interesting to see the results of further testing). It's also worth wondering if these serotinergic activities help or hurt the drug in oncology indications. In case you're wondering, the compound does get into the brain, although it's significantly effluxed by the BCRP transporter.
What I also find interesting is that this doesn't seem to have been picked up by some of the recent reports on attempts to predict and data-mine potential side effects. We still have a lot to learn, in case anyone had any doubts.
+ TrackBacks (0) | Category: Cancer | Drug Assays | The Central Nervous System | Toxicology
It's not anything to shake the earth, but I'm actually happy to see new variations being discovered for ancient reactions like the Friedel-Crafts. It makes sense that an activated amide could participate in the reaction, but it looks like no one's ever quite explored the idea like this.
And yes, I know that a large Friedel-Crafts can be a pain, what with all that aluminum gunk. The biggest one I ever ran used protic conditions (methanesulfonic acid), so I haven't had the complete experience, but I've still managed to work my way through some gooey aluminum milkshakes. But it's still a useful reaction on the bench scale.
And somehow, I can read a paper like this one and be pleased, while a paper on yet another way to dehydrate an oxime to a nitrile makes me roll my eyes. I'm still trying to work out why that might be - a bit broader scope? More possible utility? Just the fact that this was something that no one had quite thought of, as opposed to another way to take the same starting material to the same product? I should figure out what my boundaries are.
+ TrackBacks (0) | Category: Chemical News
June 22, 2012
OK, it's time to haul the marketing guys back in again. Via Pharmalot, I see that Merck, in its capacity now as Merck Schering-Plough, is promoting Claritin via a tie-in with the kid's movie "Madagascar 3". That is certainly the first time I've ever heard of a drug company co-promoting with a children's movie (or, actually, any movie at all, although I've probably missed an example or two).
And if these reports are true, the promotion is rather extensive, in an eye-rolling cringe-inducing way:
". . .customized Madagascar 3 packaging for both types of Claritin; a “Free Movie Ticket Offer” promotion with a Claritin purchase at Walgreens; the Claritin Facebook page offers a free, downloadable Madagascar Inspired Circus Activity Guide and a Madagascar themed “Circus Stackers” game; eight activity guides for free download from Facebook, and product packaging that included “5 Free Stickers” of Madagascar characters.
Merck also initiated “Children’s Claritin Mom Crew” members to hold Madagascar-themed viewing parties. Mom Crew members are bloggers who have been selected by Merck to be product endorsers, the letter states. [The Public Health Advocacy Institute at Northeastern], in fact, says it ran a Google search using the terms “Claritin mom crew Madagascar.” Of the first 40 search results, 31 were unique accounts of Children’s Claritin Madagascar viewing parties held by Claritin Mom Crew members from across the country.
Well, I just did that same search, and believe me, it's no longer the case. The Pharmalot post is now the first search result, and most of the others are unfavorable publicity in the same vein. But there certainly are accounts from the (excuse me while I hold my nose) "Claritin Mom Crew" in the results, although I'm having a lot of trouble believing that these are real blog posts that emerged from spontaneous human action. This really smells like a planned campaign, with close attention paid to phrasing, linking, and other search engine optimization techniques. For one thing, I note that every mention of this thing is carefully capitalized, and there's even a standard Twitter hashtag.
But maybe my ideas of "spontaneous human action" need to be a bit broader. There's been a long-standing technique of spreading endorsements via compensated blog posts (money, coupons, discounts, affiliate percentages), and there are surely many here's-what-I-do-with-my-kids sites that exist partly (or wholly) to reap the benefits from all these promotions. I note that at least one of these blogs is now feeling the backlash from all the negative publicity in this case, and they're probably not alone. (Roll with it, I say - after all, think of all the extra traffic you're getting!)
But this whole promotion is a rotten idea, although I suppose that you'd have to be a marketing whiz for that not to at least cross your mind. How anyone could have planned it and launched it without realizing that this backfire reaction was exactly what would surely happen is beyond me. And sure, maybe they're going to sell some more children's Claritin, briefly. But how much more, compared to all the negative PR? Compared to headline after headline that makes Merck look like the sort of organization that has no problem using cartoon character tie-ins to sell histamine receptor antagonists to kids?
Hey, why not? After all, Merck - or at least their marketing department - clearly is the sort of organization that has no problem with that at all. Own it guys - stand up and be proud. I'm sure you can manage it.
+ TrackBacks (0) | Category: Business and Markets | Why Everyone Loves Us
June 21, 2012
Now here is a piece on scientific literacy that I find interesting. The author, Daniel Sarewitz, is wondering why so many people equate it with knowing facts:
We have this belief that unless a person knows that the Earth rotates around the sun and that birds evolved from dinosaurs, she or he won’t be able to exercise responsible citizenship or participate effectively in modern society. Scientists are fond of claiming that literacy in their particular area of expertise (such as climate change or genomics) is necessary so “the public can make informed judgments on public policy issues.”
Yet the idea that we can say anything useful at all about a person's competence in the world based on their rudimentary familiarity with any particular information or type of knowledge is ridiculous. Not only is such information totally disembodied from experience and thus no more than an abstraction (and an arbitrary one at that), but it also fails to live up to what science ultimately promises: to enhance one's ability to understand and act effectively in a world of one’s knowing.
This point has often troubled me. I recall Richard Feynman's attempt to reduce the key insights of physics down to a single sentence. ("If, in some cataclysm, all of scientific knowledge were to be destroyed, and only one sentence passed on to the next generation of creatures, what statement would contain the most information in the fewest words? I believe it is the atomic hypothesis that: all things are made of atoms-little particles that that move around in perpetual motion, attracting each other when they are a little distance apart, but repelling upon being squeezed into one another. In that one sentence, you will see, there is an enormous amount of information about the world, if just a little imagination and thinking are applied") And I still can't help thinking that some basic scientific knowledge about the world is an essential part of anyone's mental furniture.
But where to stop? This is the slippery "physics for poets" problem, and I don't think it's ever been solved. Yes, everyone should know that things are made out of atoms, and that there are only a certain number of different kinds of atoms. And I'd like for people to know that living things are mostly just made out of eight or ten of those, with carbon being the most important. But at that point, are we already getting close to the borderline between knowledge and trivia? What should people know about carbon? About atomic bonds? About biomolecules? I'd like for people to know roughly what DNA is, and what proteins are, and what carbohydrates are (other than "stuff that's in food"). But in how much detail? The details multiply very, very quickly.
The same goes for any other science. A hobby of mine is astronomy, and I certainly think that everyone should know that the Earth and the other planets go around the sun, with moons that go around many of them. I'd like for them to know that the other stars are things much like our sun, and very much further away. But should people know about red giants and white dwarves and supernovas? I'd like for people to know that Jupiter is a big planet, with moons. But how many moons? Should they know the names of the Galilean satellites or not? And what good would it do them if they did?
Ah, you say, science literacy should focus not so much on the mass of facts, but on the process of doing science itself. It's a way of looking at (and learning about) the world. And I agree with that, but Sarwitz isn't letting that one off easily, either:
A more sophisticated version of science literacy that focuses not on arbitrary facts but on method or process doesn't help much, either. The canonical methods of science as taught in the classroom are powerful because they remove the phenomenon being studied from the context of the real world and isolate it in the controlled setting of the laboratory experiment. This idealized process has little if any applicability to solving the problems that people face on a daily basis, where uncertainty and indeterminacy are the rule, and effective action is based on experience and learning and accrued judgment. Textbook versions of scientific methods cannot, for example, equip a nonexpert to make an informed judgment about the validity or plausibility of technical claims made by experts.
This is overstated (I hope). The scientific technique of isolating variables is key to troubleshooting of all kinds, all the way down to problems like why the toaster oven isn't coming on. (Problem with the switch? Problem with the cord? Problem with the plug? Problem back at the circuit breaker?) And the concept of reproducibility has broad application as well. But it's true that school curricula don't always get this things across.
One of the responses to the article brings up an interesting analogy - music. There's being able to listen to music, and decide if you like it or not, or if it does anything for you. Then there's being able to read sheet music. And there's being able to play an instrument yourself, and past that, the ability to compose. When I say that I'd like for more people to know more about science, I think that I'm asking for more people to be able to the hear the music that I hear. But is that really what it means?
+ TrackBacks (0) | Category: Who Discovers and Why
Chemistry moves on, and it doesn't always take everything with it. There are reagents and reactions that used to be all over the literature, but have fallen out of use, superseded by easier or more reliable alternatives. The first thing I think of in this category is pyridinium chlorochromate (PCC), which I wrote about here. That was all the rage in the late 1970s and into the 1980s, but I don't know when I've last seen a bottle of the stuff.
And since that post itself is seven years old now, I wanted to throw the floor open again for a discussion of dead reagents and dusty reactions. There are plenty of obscure ones, of course, and plenty that don't get much use but still have their place in special situations. But I'm wondering about the ones that used to be big and now are disappearing. What are some that you used to use, but never expect to again?
For my part, other than PCC, I don't ever see doing a vanadium-catalyzed epoxidation, even though I did a few in grad school. And I recall doing a Jones oxidation - does anyone use that one any more? Another reagent that had a vogue in the late 1980s and early 1990s, but I don't recall seeing any time recently, was tris(trimethylsilyl)silane (a replacement for tri-n-butyltin hydride). So those are my nominees - what else?
+ TrackBacks (0) | Category: Life in the Drug Labs
June 20, 2012
If you're looking for the master list of business-speak cliches, look no further. That article has 89 of them, and if you can get to the end without shedding neurons from your frontal lobes, you're tougher than I am. (Note that the author of the piece recognizes this danger himself). It's a value-added, win-win paradigm shift, net-net, at the end of the day, sure to move the needle going forward. Dang. There go some of those neurons right now.
+ TrackBacks (0) | Category: Business and Markets